CHICAGO – Don’t automatically discontinue dual antiplatelet therapy for carotid endarterectomy because the neuroprotective effects may outweigh the bleeding risks, researchers concluded after a review of more than 28,000 patients who underwent the procedure during 2003-2014.

They found in the study that the 7,059 patients on perioperative dual antiplatelet therapy with clopidogrel (Plavix) and aspirin had about a 40% reduction in transient ischemic attacks (TIAs), strokes, and stroke-related deaths when compared with the 21,624 patients on aspirin alone.

The investigators found on multivariate analysis that bleeding bad enough for a return trip to the operating room was more common in their dual antiplatelet group (odds ratio, 1.73; P < .01), but they felt the neuroprotective effect was probably worth the “slightly increased bleeding risk.” Earlier research suggests that about half of vascular surgeons will discontinue clopidogrel a week or so before carotid endarterectomy (CEA) because of bleeding risks (Eur. J. Vasc. Endovasc. Surg. 2009;38:402-7).

“Although dual therapy increases perioperative bleeding, it confers an overall benefit by reducing stroke and death. Patients taking dual therapy at the time of CEA should continue treatment preoperatively. This study also suggests that initiating dual therapy is beneficial for asymptomatic patients,” lead investigator Dr. Douglas Jones of the New York Presbyterian Hospital in New York said at the meeting hosted by the Society for Vascular Surgery.

The team used the Society for Vascular Surgery’s (SVS) Vascular Quality Initiative database. Patients were about 70 years old on average and about 60% were men. Dual-therapy patients had more coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, and diabetes.

On multivariate analysis to control for those differences, dual therapy was protective against TIA or stroke (OR, 0.60; P < .01); ipsilateral TIA or stroke (OR, 0.68; P = .05); stroke (OR, 0.62; P = .04); and stroke death (OR, 0.65; P = .03). It did not protect against myocardial infarction.

“More than 95% of patients received heparin for these cases,” said Dr. Jones, noting that protamine-reversal after the case “had the greatest protective effect” against major bleeding, which is consistent with previous reports. Protamine reversal reduced it by more than 50% (OR, 0.44; P < .01).

The results, for the most part, were similar on propensity matching of 4,548 patients on dual therapy to 4,548 on aspirin alone, all of whom had CEA after 2010. Dual-therapy patients were about twice as likely to return to the operating room for bleeding (1.3% vs. 0.7%), but also had fewer thrombotic complications (for instance, stroke 0.6% vs. 1.0% in the aspirin cohort).

Asymptomatic patients on dual therapy were again about twice as likely to return to surgery for major bleeding, but half as likely to have a stroke. Bleeding was more common in symptomatic dual therapy patients, as well, but for reasons that aren’t clear, a trend toward fewer thrombotic events in symptomatic patients on propensity matching did not reach statistical significance. “The protective effect was greatest among asymptomatic patients,” Dr. Jones said.

Patients on dual therapy were also more likely to have a drain placed, but drain placement did not protect against reoperation for bleeding (OR, 1.06; P = .75).

Dr. Jones has no disclosures. Other investigators disclosed consulting fees from Medtronic, Volcano, Bard, and AnGes.

[email protected]

CHICAGO – Don’t automatically discontinue dual antiplatelet therapy for carotid endarterectomy because the neuroprotective effects may outweigh the bleeding risks, researchers concluded after a review of more than 28,000 patients who underwent the procedure during 2003-2014.

They found in the study that the 7,059 patients on perioperative dual antiplatelet therapy with clopidogrel (Plavix) and aspirin had about a 40% reduction in transient ischemic attacks (TIAs), strokes, and stroke-related deaths when compared with the 21,624 patients on aspirin alone.

The investigators found on multivariate analysis that bleeding bad enough for a return trip to the operating room was more common in their dual antiplatelet group (odds ratio, 1.73; P < .01), but they felt the neuroprotective effect was probably worth the “slightly increased bleeding risk.” Earlier research suggests that about half of vascular surgeons will discontinue clopidogrel a week or so before carotid endarterectomy (CEA) because of bleeding risks (Eur. J. Vasc. Endovasc. Surg. 2009;38:402-7).

“Although dual therapy increases perioperative bleeding, it confers an overall benefit by reducing stroke and death. Patients taking dual therapy at the time of CEA should continue treatment preoperatively. This study also suggests that initiating dual therapy is beneficial for asymptomatic patients,” lead investigator Dr. Douglas Jones of the New York Presbyterian Hospital in New York said at the meeting hosted by the Society for Vascular Surgery.

The team used the Society for Vascular Surgery’s (SVS) Vascular Quality Initiative database. Patients were about 70 years old on average and about 60% were men. Dual-therapy patients had more coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, and diabetes.

On multivariate analysis to control for those differences, dual therapy was protective against TIA or stroke (OR, 0.60; P < .01); ipsilateral TIA or stroke (OR, 0.68; P = .05); stroke (OR, 0.62; P = .04); and stroke death (OR, 0.65; P = .03). It did not protect against myocardial infarction.

“More than 95% of patients received heparin for these cases,” said Dr. Jones, noting that protamine-reversal after the case “had the greatest protective effect” against major bleeding, which is consistent with previous reports. Protamine reversal reduced it by more than 50% (OR, 0.44; P < .01).

The results, for the most part, were similar on propensity matching of 4,548 patients on dual therapy to 4,548 on aspirin alone, all of whom had CEA after 2010. Dual-therapy patients were about twice as likely to return to the operating room for bleeding (1.3% vs. 0.7%), but also had fewer thrombotic complications (for instance, stroke 0.6% vs. 1.0% in the aspirin cohort).

Asymptomatic patients on dual therapy were again about twice as likely to return to surgery for major bleeding, but half as likely to have a stroke. Bleeding was more common in symptomatic dual therapy patients, as well, but for reasons that aren’t clear, a trend toward fewer thrombotic events in symptomatic patients on propensity matching did not reach statistical significance. “The protective effect was greatest among asymptomatic patients,” Dr. Jones said.

Patients on dual therapy were also more likely to have a drain placed, but drain placement did not protect against reoperation for bleeding (OR, 1.06; P = .75).

Dr. Jones has no disclosures. Other investigators disclosed consulting fees from Medtronic, Volcano, Bard, and AnGes.

[email protected]

CHICAGO – Don’t automatically discontinue dual antiplatelet therapy for carotid endarterectomy because the neuroprotective effects may outweigh the bleeding risks, researchers concluded after a review of more than 28,000 patients who underwent the procedure during 2003-2014.

They found in the study that the 7,059 patients on perioperative dual antiplatelet therapy with clopidogrel (Plavix) and aspirin had about a 40% reduction in transient ischemic attacks (TIAs), strokes, and stroke-related deaths when compared with the 21,624 patients on aspirin alone.

The investigators found on multivariate analysis that bleeding bad enough for a return trip to the operating room was more common in their dual antiplatelet group (odds ratio, 1.73; P < .01), but they felt the neuroprotective effect was probably worth the “slightly increased bleeding risk.” Earlier research suggests that about half of vascular surgeons will discontinue clopidogrel a week or so before carotid endarterectomy (CEA) because of bleeding risks (Eur. J. Vasc. Endovasc. Surg. 2009;38:402-7).

“Although dual therapy increases perioperative bleeding, it confers an overall benefit by reducing stroke and death. Patients taking dual therapy at the time of CEA should continue treatment preoperatively. This study also suggests that initiating dual therapy is beneficial for asymptomatic patients,” lead investigator Dr. Douglas Jones of the New York Presbyterian Hospital in New York said at the meeting hosted by the Society for Vascular Surgery.

The team used the Society for Vascular Surgery’s (SVS) Vascular Quality Initiative database. Patients were about 70 years old on average and about 60% were men. Dual-therapy patients had more coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, and diabetes.

On multivariate analysis to control for those differences, dual therapy was protective against TIA or stroke (OR, 0.60; P < .01); ipsilateral TIA or stroke (OR, 0.68; P = .05); stroke (OR, 0.62; P = .04); and stroke death (OR, 0.65; P = .03). It did not protect against myocardial infarction.

“More than 95% of patients received heparin for these cases,” said Dr. Jones, noting that protamine-reversal after the case “had the greatest protective effect” against major bleeding, which is consistent with previous reports. Protamine reversal reduced it by more than 50% (OR, 0.44; P < .01).

The results, for the most part, were similar on propensity matching of 4,548 patients on dual therapy to 4,548 on aspirin alone, all of whom had CEA after 2010. Dual-therapy patients were about twice as likely to return to the operating room for bleeding (1.3% vs. 0.7%), but also had fewer thrombotic complications (for instance, stroke 0.6% vs. 1.0% in the aspirin cohort).

Asymptomatic patients on dual therapy were again about twice as likely to return to surgery for major bleeding, but half as likely to have a stroke. Bleeding was more common in symptomatic dual therapy patients, as well, but for reasons that aren’t clear, a trend toward fewer thrombotic events in symptomatic patients on propensity matching did not reach statistical significance. “The protective effect was greatest among asymptomatic patients,” Dr. Jones said.

Patients on dual therapy were also more likely to have a drain placed, but drain placement did not protect against reoperation for bleeding (OR, 1.06; P = .75).

Dr. Jones has no disclosures. Other investigators disclosed consulting fees from Medtronic, Volcano, Bard, and AnGes.

[email protected]

Blood clot formation

Image by James Weaver

The US Food and Drug Administration (FDA) has granted 501(k) clearance for the Hemogrip Patch, a product used to treat uncontrolled hemorrhage.

The patch is designed to control bleeding that occurs when accessing veins or arteries for various medical treatments and applications.

The Hemogrip platform technology is based on chitosan, a natural biopolymer found in the exoskeleton of crustaceans.

Chitosan is biocompatible, anti-microbial, and durable under a range of environmental conditions.

When applied to wounds, Hemogrip creates a nano-scale, 3-dimensional mesh, rapidly coagulating blood and stopping blood loss.

Hemogrip technology has proven effective in a study of swine, halting uncontrolled hemorrhage in a model of lethal arterial injury. Other in vivo research showed that Hemogrip’s hemostatic effects are reversible.

The Hemogrip Patch is under development by the medical device company Remedium Technologies, a spin-out of the University of Maryland.

Blood clot formation

Image by James Weaver

The US Food and Drug Administration (FDA) has granted 501(k) clearance for the Hemogrip Patch, a product used to treat uncontrolled hemorrhage.

The patch is designed to control bleeding that occurs when accessing veins or arteries for various medical treatments and applications.

The Hemogrip platform technology is based on chitosan, a natural biopolymer found in the exoskeleton of crustaceans.

Chitosan is biocompatible, anti-microbial, and durable under a range of environmental conditions.

When applied to wounds, Hemogrip creates a nano-scale, 3-dimensional mesh, rapidly coagulating blood and stopping blood loss.

Hemogrip technology has proven effective in a study of swine, halting uncontrolled hemorrhage in a model of lethal arterial injury. Other in vivo research showed that Hemogrip’s hemostatic effects are reversible.

The Hemogrip Patch is under development by the medical device company Remedium Technologies, a spin-out of the University of Maryland.

Blood clot formation

Image by James Weaver

The US Food and Drug Administration (FDA) has granted 501(k) clearance for the Hemogrip Patch, a product used to treat uncontrolled hemorrhage.

The patch is designed to control bleeding that occurs when accessing veins or arteries for various medical treatments and applications.

The Hemogrip platform technology is based on chitosan, a natural biopolymer found in the exoskeleton of crustaceans.

Chitosan is biocompatible, anti-microbial, and durable under a range of environmental conditions.

When applied to wounds, Hemogrip creates a nano-scale, 3-dimensional mesh, rapidly coagulating blood and stopping blood loss.

Hemogrip technology has proven effective in a study of swine, halting uncontrolled hemorrhage in a model of lethal arterial injury. Other in vivo research showed that Hemogrip’s hemostatic effects are reversible.

The Hemogrip Patch is under development by the medical device company Remedium Technologies, a spin-out of the University of Maryland.

Long-term survival after hematopoietic stem cell transplantation for infantile osteopetrosis was highest when grafts were taken from human leukocyte antigen (HLA)-matched siblings, according to the largest cohort of patients with the disease that has been compiled to date.

For HLA-matched sibling transplants, 5- and 10-year survival probabilities were both 62%, whereas the combined average survival probability for HLA-mismatched relative donors, HLA-matched unrelated donors, and HLA-unmatched unrelated donors was 42% after 5 years and 39% after 10 years, Dr. Paul J. Orchard of the University of Minnesota, Minneapolis, and his colleagues reported.

Of surviving patients, 70% have visual impairment and 10% have auditory impairment and motor delay. Despite this, most survivors are attending a public or specialized school, and 65% of survivors reported performance scores of 90 or 100 at last contact, the investigators said.

Graft failure was the most common cause of death, occurring in 50% of HLA-matched sibling transplant patients and in 43% of alternative HLA transplant patients. Veno-occlusive disease and interstitial pneumonitis rates were also high, both at about 20%.

“There is an urgent need to improve engraftment by developing novel strategies that target the microenvironment and study the association between genetic variants of osteopetrosis and transplantation outcomes,” the researchers said.

Find the full article in the July 9 issue of Blood (Blood 2015;126:270-6).

[email protected]

Long-term survival after hematopoietic stem cell transplantation for infantile osteopetrosis was highest when grafts were taken from human leukocyte antigen (HLA)-matched siblings, according to the largest cohort of patients with the disease that has been compiled to date.

For HLA-matched sibling transplants, 5- and 10-year survival probabilities were both 62%, whereas the combined average survival probability for HLA-mismatched relative donors, HLA-matched unrelated donors, and HLA-unmatched unrelated donors was 42% after 5 years and 39% after 10 years, Dr. Paul J. Orchard of the University of Minnesota, Minneapolis, and his colleagues reported.

Of surviving patients, 70% have visual impairment and 10% have auditory impairment and motor delay. Despite this, most survivors are attending a public or specialized school, and 65% of survivors reported performance scores of 90 or 100 at last contact, the investigators said.

Graft failure was the most common cause of death, occurring in 50% of HLA-matched sibling transplant patients and in 43% of alternative HLA transplant patients. Veno-occlusive disease and interstitial pneumonitis rates were also high, both at about 20%.

“There is an urgent need to improve engraftment by developing novel strategies that target the microenvironment and study the association between genetic variants of osteopetrosis and transplantation outcomes,” the researchers said.

Find the full article in the July 9 issue of Blood (Blood 2015;126:270-6).

[email protected]

Long-term survival after hematopoietic stem cell transplantation for infantile osteopetrosis was highest when grafts were taken from human leukocyte antigen (HLA)-matched siblings, according to the largest cohort of patients with the disease that has been compiled to date.

For HLA-matched sibling transplants, 5- and 10-year survival probabilities were both 62%, whereas the combined average survival probability for HLA-mismatched relative donors, HLA-matched unrelated donors, and HLA-unmatched unrelated donors was 42% after 5 years and 39% after 10 years, Dr. Paul J. Orchard of the University of Minnesota, Minneapolis, and his colleagues reported.

Of surviving patients, 70% have visual impairment and 10% have auditory impairment and motor delay. Despite this, most survivors are attending a public or specialized school, and 65% of survivors reported performance scores of 90 or 100 at last contact, the investigators said.

Graft failure was the most common cause of death, occurring in 50% of HLA-matched sibling transplant patients and in 43% of alternative HLA transplant patients. Veno-occlusive disease and interstitial pneumonitis rates were also high, both at about 20%.

“There is an urgent need to improve engraftment by developing novel strategies that target the microenvironment and study the association between genetic variants of osteopetrosis and transplantation outcomes,” the researchers said.

Find the full article in the July 9 issue of Blood (Blood 2015;126:270-6).

[email protected]

VIENNA – Patients with high-risk newly diagnosed acute promyelocytic leukemia derive the same survival benefit from a chemotherapy-free combination as an anthracycline-containing standard of care, according to results of the AML17 APL study.

The 4-year overall survival rates in high-risk patients (WBC > 10 x 10⁹/L) were 87% with arsenic trioxide plus all-trans retinoic acid and 84% with the standard all-trans retinoic acid and idarubicin schedule.

Relapse-free survival rates were superior with the chemotherapy-free combination (100% vs. 74%; P = .008), Dr. Alan Burnett reported at the annual congress of the European Hematology Association.

“One of our rationales for using arsenic as first-line (therapy) was to try and get at the early death that remains a major problem in this disease,” he said.

Arsenic trioxide and gemtuzumab ozogamicin are effective as single agents with the former approved for relapsed disease in patients with APL. The GIMEMA-AMLSG-SAL trial indicated that a daily schedule of arsenic trioxide plus all-trans retinoic acid was at least as effective and may be superior to all-trans retinoic acid plus chemotherapy in low to moderate risk APL patients (N. Engl. J. Med. 2013;369: 111-21).

The AML17 APL trial was designed by the U.K. National Cancer Research Institute with the aim of comparing all-trans retinoic acid and idarubicin with arsenic trioxide in an attenuated dosing schedule plus all-trans retinoic acid. Importantly, high-risk patients were included, with the option to receive a single dose of gemtuzumab ozogamicin (Mylotarg) 6 mg/m² within the first 4 days of induction, said Dr. Burnett, who performed the research as head of hematology at Cardiff University in Wales and is now global lead for myeloid diseases at CTI BioPharma in Seattle. In the United States, gemtuzumab was withdrawn from the market in 2010 because of safety concerns.

From May 2009 to October 2013, 235 patients with molecularly confirmed APL were randomized at 81 centers to all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60 or complete remission plus arsenic trioxide 0.3 mg/kg on days 1-5 of week 1 and then 0.25 mg/kg twice per week for 7 weeks plus all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60 or complete remission or to idarubicin 12 mg/m² on days 2, 4, 6, 8 plus all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60.

In the arsenic trioxide plus all-trans retinoic acid arm, this was followed by all-trans retinoic acid 45 mg/m² as a divided daily dose 2 weeks on and 2 weeks off plus four consolidation courses of arsenic trioxide 0.3 mg/kg days 1-5 of week 1 and then 0.25 mg/kg twice per week for 3 weeks (total 63 days of arsenic trioxide).

Consolidation in the all-trans retinoic acid and idarubicin arm was all-trans retinoic acid 45 mg/m² as a divided daily dose on days 1-15 plus idarubicin 5 mg/m² days 1-4 in course 2, mitoxantrone 10mg/m² days 1-4 in course 3, and idarubicin 12 mg/m² day 1 in course 4.

No maintenance was given in either arm. The median patient age was 47 years, with about 20% of patients over age 60; over 20% of the patients were high-risk, and they were equally balanced in the two treatment groups.

At 4 years, the overall survival rate among all patients was comparable – 93% with arsenic trioxide plus all-trans retinoic acid and 89% with all-trans retinoic acid and idarubicin.

However, event-free survival was significantly better in the arsenic trioxide plus all-trans retinoic acid cohort (91% vs. 74%; hazard ratio, 0.36; P = .003), as were frank relapse-free survival (97% vs. 83%; HR, 0.24; P = .004) and molecular relapse-free survival (98% vs. 70%; HR, 0.17; P < .0001), Dr. Burnett said.

One patient on arsenic trioxide plus all-trans retinoic acid experienced frank relapse, compared with 13 on all-trans retinoic acid and idarubicin, plus a further 19 molecular relapses occurred on this arm (cumulative incidence of molecular and hematologic relapse 0% vs. 27%, HR, 0.12; P < .0001).

“Once a patient was in molecular remission there were no further relapses in patients on (arsenic trioxide plus all-trans retinoic acid),” he said.

Of the 30 high-risk patients allocated to the chemo-free arm, 28 received gemtuzumab ozogamicin as per protocol. The overall survival at 4 years for these patients was 89%. Of the two patients not treated with gemtuzumab ozogamicin, one died on day 12 due to causes unrelated to treatment.

Among the 49 patients older than 60 years, overall survival was 80% with arsenic trioxide plus all-trans retinoic acid and 74% with all-trans retinoic acid and idarubicin. Similarly, among good-risk patients, relapse-free survival was significantly improved (96% vs. 79%; HR, 0.33; P = .04). Also, overall survival was not inferior at 95% vs. 90%, “very much replicating the outcomes seen in the GIMEMA study,” Dr. Burnett said.

The benefits were also achieved with significantly less grade 3-4 liver toxicity than observed in the GIMEMA study (<10% vs 63%).

There was, however, an excess of cardiac toxicity in course 2 with arsenic trioxide plus all-trans retinoic acid, compared with all-trans retinoic acid and idarubicin (P = .001).

“We’re not totally sure what that’s all due to, but it doesn’t look to be due to a QC prolongation,” he said.

The arsenic trioxide plus all-trans retinoic acid regimen was associated with significant reductions in supportive care requirements including fewer blood and platelet transfusions, days on antibiotics, and days in hospital, with “many patients treated exclusively as outpatients,” he added.

The low risk of relapse with arsenic trioxide plus all-trans retinoic acid also negates the need for minimal residual disease monitoring.

Finally, compared with the GIMEMA study protocol, the attenuated arsenic dosing schedule in AML17 APL resulted in less frequent dosing of arsenic trioxide (63 doses vs. 140 doses) and less drug required (151 vials vs. 280 vials for a 70-kg patient). At an acquisition cost of £350 per vial, this represents a cost savings of £46,000 (nearly $72,000) per patient, not to mention the added convenience to patients, Dr. Burnett observed.

Cancer Research U.K. funded the study. Cephalon provided the arsenic trioxide. Dr. Burnett disclosed part-time employment with CTI LifeSciences and in the last 12 months serving on the advisory boards of Celgene, Agios, Pfizer, and Bristol-Myers Squibb.

[email protected]

VIENNA – Patients with high-risk newly diagnosed acute promyelocytic leukemia derive the same survival benefit from a chemotherapy-free combination as an anthracycline-containing standard of care, according to results of the AML17 APL study.

The 4-year overall survival rates in high-risk patients (WBC > 10 x 10⁹/L) were 87% with arsenic trioxide plus all-trans retinoic acid and 84% with the standard all-trans retinoic acid and idarubicin schedule.

Relapse-free survival rates were superior with the chemotherapy-free combination (100% vs. 74%; P = .008), Dr. Alan Burnett reported at the annual congress of the European Hematology Association.

“One of our rationales for using arsenic as first-line (therapy) was to try and get at the early death that remains a major problem in this disease,” he said.

Arsenic trioxide and gemtuzumab ozogamicin are effective as single agents with the former approved for relapsed disease in patients with APL. The GIMEMA-AMLSG-SAL trial indicated that a daily schedule of arsenic trioxide plus all-trans retinoic acid was at least as effective and may be superior to all-trans retinoic acid plus chemotherapy in low to moderate risk APL patients (N. Engl. J. Med. 2013;369: 111-21).

The AML17 APL trial was designed by the U.K. National Cancer Research Institute with the aim of comparing all-trans retinoic acid and idarubicin with arsenic trioxide in an attenuated dosing schedule plus all-trans retinoic acid. Importantly, high-risk patients were included, with the option to receive a single dose of gemtuzumab ozogamicin (Mylotarg) 6 mg/m² within the first 4 days of induction, said Dr. Burnett, who performed the research as head of hematology at Cardiff University in Wales and is now global lead for myeloid diseases at CTI BioPharma in Seattle. In the United States, gemtuzumab was withdrawn from the market in 2010 because of safety concerns.

From May 2009 to October 2013, 235 patients with molecularly confirmed APL were randomized at 81 centers to all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60 or complete remission plus arsenic trioxide 0.3 mg/kg on days 1-5 of week 1 and then 0.25 mg/kg twice per week for 7 weeks plus all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60 or complete remission or to idarubicin 12 mg/m² on days 2, 4, 6, 8 plus all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60.

In the arsenic trioxide plus all-trans retinoic acid arm, this was followed by all-trans retinoic acid 45 mg/m² as a divided daily dose 2 weeks on and 2 weeks off plus four consolidation courses of arsenic trioxide 0.3 mg/kg days 1-5 of week 1 and then 0.25 mg/kg twice per week for 3 weeks (total 63 days of arsenic trioxide).

Consolidation in the all-trans retinoic acid and idarubicin arm was all-trans retinoic acid 45 mg/m² as a divided daily dose on days 1-15 plus idarubicin 5 mg/m² days 1-4 in course 2, mitoxantrone 10mg/m² days 1-4 in course 3, and idarubicin 12 mg/m² day 1 in course 4.

No maintenance was given in either arm. The median patient age was 47 years, with about 20% of patients over age 60; over 20% of the patients were high-risk, and they were equally balanced in the two treatment groups.

At 4 years, the overall survival rate among all patients was comparable – 93% with arsenic trioxide plus all-trans retinoic acid and 89% with all-trans retinoic acid and idarubicin.

However, event-free survival was significantly better in the arsenic trioxide plus all-trans retinoic acid cohort (91% vs. 74%; hazard ratio, 0.36; P = .003), as were frank relapse-free survival (97% vs. 83%; HR, 0.24; P = .004) and molecular relapse-free survival (98% vs. 70%; HR, 0.17; P < .0001), Dr. Burnett said.

One patient on arsenic trioxide plus all-trans retinoic acid experienced frank relapse, compared with 13 on all-trans retinoic acid and idarubicin, plus a further 19 molecular relapses occurred on this arm (cumulative incidence of molecular and hematologic relapse 0% vs. 27%, HR, 0.12; P < .0001).

“Once a patient was in molecular remission there were no further relapses in patients on (arsenic trioxide plus all-trans retinoic acid),” he said.

Of the 30 high-risk patients allocated to the chemo-free arm, 28 received gemtuzumab ozogamicin as per protocol. The overall survival at 4 years for these patients was 89%. Of the two patients not treated with gemtuzumab ozogamicin, one died on day 12 due to causes unrelated to treatment.

Among the 49 patients older than 60 years, overall survival was 80% with arsenic trioxide plus all-trans retinoic acid and 74% with all-trans retinoic acid and idarubicin. Similarly, among good-risk patients, relapse-free survival was significantly improved (96% vs. 79%; HR, 0.33; P = .04). Also, overall survival was not inferior at 95% vs. 90%, “very much replicating the outcomes seen in the GIMEMA study,” Dr. Burnett said.

The benefits were also achieved with significantly less grade 3-4 liver toxicity than observed in the GIMEMA study (<10% vs 63%).

There was, however, an excess of cardiac toxicity in course 2 with arsenic trioxide plus all-trans retinoic acid, compared with all-trans retinoic acid and idarubicin (P = .001).

“We’re not totally sure what that’s all due to, but it doesn’t look to be due to a QC prolongation,” he said.

The arsenic trioxide plus all-trans retinoic acid regimen was associated with significant reductions in supportive care requirements including fewer blood and platelet transfusions, days on antibiotics, and days in hospital, with “many patients treated exclusively as outpatients,” he added.

The low risk of relapse with arsenic trioxide plus all-trans retinoic acid also negates the need for minimal residual disease monitoring.

Finally, compared with the GIMEMA study protocol, the attenuated arsenic dosing schedule in AML17 APL resulted in less frequent dosing of arsenic trioxide (63 doses vs. 140 doses) and less drug required (151 vials vs. 280 vials for a 70-kg patient). At an acquisition cost of £350 per vial, this represents a cost savings of £46,000 (nearly $72,000) per patient, not to mention the added convenience to patients, Dr. Burnett observed.

Cancer Research U.K. funded the study. Cephalon provided the arsenic trioxide. Dr. Burnett disclosed part-time employment with CTI LifeSciences and in the last 12 months serving on the advisory boards of Celgene, Agios, Pfizer, and Bristol-Myers Squibb.

[email protected]

VIENNA – Patients with high-risk newly diagnosed acute promyelocytic leukemia derive the same survival benefit from a chemotherapy-free combination as an anthracycline-containing standard of care, according to results of the AML17 APL study.

The 4-year overall survival rates in high-risk patients (WBC > 10 x 10⁹/L) were 87% with arsenic trioxide plus all-trans retinoic acid and 84% with the standard all-trans retinoic acid and idarubicin schedule.

Relapse-free survival rates were superior with the chemotherapy-free combination (100% vs. 74%; P = .008), Dr. Alan Burnett reported at the annual congress of the European Hematology Association.

“One of our rationales for using arsenic as first-line (therapy) was to try and get at the early death that remains a major problem in this disease,” he said.

Arsenic trioxide and gemtuzumab ozogamicin are effective as single agents with the former approved for relapsed disease in patients with APL. The GIMEMA-AMLSG-SAL trial indicated that a daily schedule of arsenic trioxide plus all-trans retinoic acid was at least as effective and may be superior to all-trans retinoic acid plus chemotherapy in low to moderate risk APL patients (N. Engl. J. Med. 2013;369: 111-21).

The AML17 APL trial was designed by the U.K. National Cancer Research Institute with the aim of comparing all-trans retinoic acid and idarubicin with arsenic trioxide in an attenuated dosing schedule plus all-trans retinoic acid. Importantly, high-risk patients were included, with the option to receive a single dose of gemtuzumab ozogamicin (Mylotarg) 6 mg/m² within the first 4 days of induction, said Dr. Burnett, who performed the research as head of hematology at Cardiff University in Wales and is now global lead for myeloid diseases at CTI BioPharma in Seattle. In the United States, gemtuzumab was withdrawn from the market in 2010 because of safety concerns.

From May 2009 to October 2013, 235 patients with molecularly confirmed APL were randomized at 81 centers to all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60 or complete remission plus arsenic trioxide 0.3 mg/kg on days 1-5 of week 1 and then 0.25 mg/kg twice per week for 7 weeks plus all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60 or complete remission or to idarubicin 12 mg/m² on days 2, 4, 6, 8 plus all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60.

In the arsenic trioxide plus all-trans retinoic acid arm, this was followed by all-trans retinoic acid 45 mg/m² as a divided daily dose 2 weeks on and 2 weeks off plus four consolidation courses of arsenic trioxide 0.3 mg/kg days 1-5 of week 1 and then 0.25 mg/kg twice per week for 3 weeks (total 63 days of arsenic trioxide).

Consolidation in the all-trans retinoic acid and idarubicin arm was all-trans retinoic acid 45 mg/m² as a divided daily dose on days 1-15 plus idarubicin 5 mg/m² days 1-4 in course 2, mitoxantrone 10mg/m² days 1-4 in course 3, and idarubicin 12 mg/m² day 1 in course 4.

No maintenance was given in either arm. The median patient age was 47 years, with about 20% of patients over age 60; over 20% of the patients were high-risk, and they were equally balanced in the two treatment groups.

At 4 years, the overall survival rate among all patients was comparable – 93% with arsenic trioxide plus all-trans retinoic acid and 89% with all-trans retinoic acid and idarubicin.

However, event-free survival was significantly better in the arsenic trioxide plus all-trans retinoic acid cohort (91% vs. 74%; hazard ratio, 0.36; P = .003), as were frank relapse-free survival (97% vs. 83%; HR, 0.24; P = .004) and molecular relapse-free survival (98% vs. 70%; HR, 0.17; P < .0001), Dr. Burnett said.

One patient on arsenic trioxide plus all-trans retinoic acid experienced frank relapse, compared with 13 on all-trans retinoic acid and idarubicin, plus a further 19 molecular relapses occurred on this arm (cumulative incidence of molecular and hematologic relapse 0% vs. 27%, HR, 0.12; P < .0001).

“Once a patient was in molecular remission there were no further relapses in patients on (arsenic trioxide plus all-trans retinoic acid),” he said.

Of the 30 high-risk patients allocated to the chemo-free arm, 28 received gemtuzumab ozogamicin as per protocol. The overall survival at 4 years for these patients was 89%. Of the two patients not treated with gemtuzumab ozogamicin, one died on day 12 due to causes unrelated to treatment.

Among the 49 patients older than 60 years, overall survival was 80% with arsenic trioxide plus all-trans retinoic acid and 74% with all-trans retinoic acid and idarubicin. Similarly, among good-risk patients, relapse-free survival was significantly improved (96% vs. 79%; HR, 0.33; P = .04). Also, overall survival was not inferior at 95% vs. 90%, “very much replicating the outcomes seen in the GIMEMA study,” Dr. Burnett said.

The benefits were also achieved with significantly less grade 3-4 liver toxicity than observed in the GIMEMA study (<10% vs 63%).

There was, however, an excess of cardiac toxicity in course 2 with arsenic trioxide plus all-trans retinoic acid, compared with all-trans retinoic acid and idarubicin (P = .001).

“We’re not totally sure what that’s all due to, but it doesn’t look to be due to a QC prolongation,” he said.

The arsenic trioxide plus all-trans retinoic acid regimen was associated with significant reductions in supportive care requirements including fewer blood and platelet transfusions, days on antibiotics, and days in hospital, with “many patients treated exclusively as outpatients,” he added.

The low risk of relapse with arsenic trioxide plus all-trans retinoic acid also negates the need for minimal residual disease monitoring.

Finally, compared with the GIMEMA study protocol, the attenuated arsenic dosing schedule in AML17 APL resulted in less frequent dosing of arsenic trioxide (63 doses vs. 140 doses) and less drug required (151 vials vs. 280 vials for a 70-kg patient). At an acquisition cost of £350 per vial, this represents a cost savings of £46,000 (nearly $72,000) per patient, not to mention the added convenience to patients, Dr. Burnett observed.

Cancer Research U.K. funded the study. Cephalon provided the arsenic trioxide. Dr. Burnett disclosed part-time employment with CTI LifeSciences and in the last 12 months serving on the advisory boards of Celgene, Agios, Pfizer, and Bristol-Myers Squibb.

[email protected]

Antihemophilic factor

An investigational recombinant factor VIII (rFVIII) product can safely treat and prevent bleeding in previously treated patients with hemophilia A, according to researchers.

The product, BAX 855, is a pegylated version of ADVATE, a full-length rFVIII product already approved to treat hemophilia A.

BAX 855 was designed to have a longer half-life than ADVATE, thereby allowing for fewer prophylactic infusions without affecting hemostatic efficacy.

Results of a phase 1 study showed that BAX 855 had a longer half-life and mean residence time than ADVATE. And results of a phase 2/3 study showed that twice-weekly prophylactic treatment with BAX 855 lowered the median annualized bleed rate (ABR) when compared to on-demand treatment with BAX 855.

None of the patients who received BAX 855 in either study developed inhibitors, and there were no serious adverse events (AEs) that were considered treatment-related.

Results from both trials were published in Blood. The research was funded by Baxalta, a spin-off of Baxter Healthcare Corporation.

Study characteristics

The phase 1 study included 19 previously treated patients with severe hemophilia A and a median age of 29 (range, 18-60). The patients received single infusions of ADVATE followed by BAX 855 (after a wash-out period) at 30 IU/kg or 60 IU/kg.

In the phase 2/3 trial, researchers evaluated BAX 855 in 137 previously treated patients with hemophilia A. These patients also had a median age of 29 (range, 12-58).

They were assigned to either twice-weekly prophylaxis (40-50 IU/kg, n=120) or on-demand treatment (10-60 IU/kg, n=17) with BAX 855. One hundred and twenty-six patients completed the study.

Pharmacokinetics and safety

In the phase 1 study, the mean residence time was higher with BAX 855 than with ADVATE—1.4-fold higher in the 30 IU/kg arm and 1.5-fold higher in the 60 IU/kg arm. The mean half-life was higher with BAX 855 as well—1.4-fold higher in the 30 IU/kg arm and 1.5-fold in the 60 IU/kg arm.

Results were similar in the phase 2/3 trial.

None of the subjects in the phase 1 study experienced a serious AE after their single infusion of BAX 855. Eight patients experienced a total of 11 non-serious AEs, none of which were considered related to BAX 855.

In the phase 2/3 study, there were 171 AEs in 73 patients who received BAX 855 for about 6 months. There were 7 AEs (occurring in 6 patients) that were considered possibly related to BAX 855. These included diarrhea, nausea, headache, and flushing.

There were 5 serious AEs (occurring in 5 patients) that were not considered treatment-related. These included osteoarthritis, herpes zoster infection, humerus fracture, neuroendocrine carcinoma, and muscle hemorrhage.

Efficacy: Prophylaxis and on-demand

The researchers only assessed the efficacy of BAX 855 prophylaxis and on-demand treatment in the phase 2/3 study.

Patients received a median dose of 44.6 IU/kg per prophylactic infusion. The mean reduction in dosing frequency from pre-study prophylaxis was 26.7%, and 70.4% of patients were able to reduce the frequency of dosing by 30% or more. This is roughly equivalent to at least 1 less prophylactic infusion per week.

Patients who received prophylaxis had a 90% reduction in ABR compared to those who received on-demand treatment. The median ABR was 1.9 in the prophylactic arm and 41.5 in the on-demand arm.

The ABRs for joint bleeds or spontaneous/unknown bleeds were both 0 in the prophylactic arm, compared to 38.1 and 21.6, respectively, in the on-demand treatment arm.

Patients who received on-demand treatment were given a median dose of 30.87 IU/kg per episode and 29.19 IU/kg for the maintenance of hemostasis.

Of the 518 bleeding episodes reported during the study, 95.9% were treated with 1 or 2 infusions of BAX 855. The mean number of infusions required to treat a bleeding episode was 1.2.

Antihemophilic factor

An investigational recombinant factor VIII (rFVIII) product can safely treat and prevent bleeding in previously treated patients with hemophilia A, according to researchers.

The product, BAX 855, is a pegylated version of ADVATE, a full-length rFVIII product already approved to treat hemophilia A.

BAX 855 was designed to have a longer half-life than ADVATE, thereby allowing for fewer prophylactic infusions without affecting hemostatic efficacy.

Results of a phase 1 study showed that BAX 855 had a longer half-life and mean residence time than ADVATE. And results of a phase 2/3 study showed that twice-weekly prophylactic treatment with BAX 855 lowered the median annualized bleed rate (ABR) when compared to on-demand treatment with BAX 855.

None of the patients who received BAX 855 in either study developed inhibitors, and there were no serious adverse events (AEs) that were considered treatment-related.

Results from both trials were published in Blood. The research was funded by Baxalta, a spin-off of Baxter Healthcare Corporation.

Study characteristics

The phase 1 study included 19 previously treated patients with severe hemophilia A and a median age of 29 (range, 18-60). The patients received single infusions of ADVATE followed by BAX 855 (after a wash-out period) at 30 IU/kg or 60 IU/kg.

In the phase 2/3 trial, researchers evaluated BAX 855 in 137 previously treated patients with hemophilia A. These patients also had a median age of 29 (range, 12-58).

They were assigned to either twice-weekly prophylaxis (40-50 IU/kg, n=120) or on-demand treatment (10-60 IU/kg, n=17) with BAX 855. One hundred and twenty-six patients completed the study.

Pharmacokinetics and safety

In the phase 1 study, the mean residence time was higher with BAX 855 than with ADVATE—1.4-fold higher in the 30 IU/kg arm and 1.5-fold higher in the 60 IU/kg arm. The mean half-life was higher with BAX 855 as well—1.4-fold higher in the 30 IU/kg arm and 1.5-fold in the 60 IU/kg arm.

Results were similar in the phase 2/3 trial.

None of the subjects in the phase 1 study experienced a serious AE after their single infusion of BAX 855. Eight patients experienced a total of 11 non-serious AEs, none of which were considered related to BAX 855.

In the phase 2/3 study, there were 171 AEs in 73 patients who received BAX 855 for about 6 months. There were 7 AEs (occurring in 6 patients) that were considered possibly related to BAX 855. These included diarrhea, nausea, headache, and flushing.

There were 5 serious AEs (occurring in 5 patients) that were not considered treatment-related. These included osteoarthritis, herpes zoster infection, humerus fracture, neuroendocrine carcinoma, and muscle hemorrhage.

Efficacy: Prophylaxis and on-demand

The researchers only assessed the efficacy of BAX 855 prophylaxis and on-demand treatment in the phase 2/3 study.

Patients received a median dose of 44.6 IU/kg per prophylactic infusion. The mean reduction in dosing frequency from pre-study prophylaxis was 26.7%, and 70.4% of patients were able to reduce the frequency of dosing by 30% or more. This is roughly equivalent to at least 1 less prophylactic infusion per week.

Patients who received prophylaxis had a 90% reduction in ABR compared to those who received on-demand treatment. The median ABR was 1.9 in the prophylactic arm and 41.5 in the on-demand arm.

The ABRs for joint bleeds or spontaneous/unknown bleeds were both 0 in the prophylactic arm, compared to 38.1 and 21.6, respectively, in the on-demand treatment arm.

Patients who received on-demand treatment were given a median dose of 30.87 IU/kg per episode and 29.19 IU/kg for the maintenance of hemostasis.

Of the 518 bleeding episodes reported during the study, 95.9% were treated with 1 or 2 infusions of BAX 855. The mean number of infusions required to treat a bleeding episode was 1.2.

Antihemophilic factor

An investigational recombinant factor VIII (rFVIII) product can safely treat and prevent bleeding in previously treated patients with hemophilia A, according to researchers.

The product, BAX 855, is a pegylated version of ADVATE, a full-length rFVIII product already approved to treat hemophilia A.

BAX 855 was designed to have a longer half-life than ADVATE, thereby allowing for fewer prophylactic infusions without affecting hemostatic efficacy.

Results of a phase 1 study showed that BAX 855 had a longer half-life and mean residence time than ADVATE. And results of a phase 2/3 study showed that twice-weekly prophylactic treatment with BAX 855 lowered the median annualized bleed rate (ABR) when compared to on-demand treatment with BAX 855.

None of the patients who received BAX 855 in either study developed inhibitors, and there were no serious adverse events (AEs) that were considered treatment-related.

Results from both trials were published in Blood. The research was funded by Baxalta, a spin-off of Baxter Healthcare Corporation.

Study characteristics

The phase 1 study included 19 previously treated patients with severe hemophilia A and a median age of 29 (range, 18-60). The patients received single infusions of ADVATE followed by BAX 855 (after a wash-out period) at 30 IU/kg or 60 IU/kg.

In the phase 2/3 trial, researchers evaluated BAX 855 in 137 previously treated patients with hemophilia A. These patients also had a median age of 29 (range, 12-58).

They were assigned to either twice-weekly prophylaxis (40-50 IU/kg, n=120) or on-demand treatment (10-60 IU/kg, n=17) with BAX 855. One hundred and twenty-six patients completed the study.

Pharmacokinetics and safety

In the phase 1 study, the mean residence time was higher with BAX 855 than with ADVATE—1.4-fold higher in the 30 IU/kg arm and 1.5-fold higher in the 60 IU/kg arm. The mean half-life was higher with BAX 855 as well—1.4-fold higher in the 30 IU/kg arm and 1.5-fold in the 60 IU/kg arm.

Results were similar in the phase 2/3 trial.

None of the subjects in the phase 1 study experienced a serious AE after their single infusion of BAX 855. Eight patients experienced a total of 11 non-serious AEs, none of which were considered related to BAX 855.

In the phase 2/3 study, there were 171 AEs in 73 patients who received BAX 855 for about 6 months. There were 7 AEs (occurring in 6 patients) that were considered possibly related to BAX 855. These included diarrhea, nausea, headache, and flushing.

There were 5 serious AEs (occurring in 5 patients) that were not considered treatment-related. These included osteoarthritis, herpes zoster infection, humerus fracture, neuroendocrine carcinoma, and muscle hemorrhage.

Efficacy: Prophylaxis and on-demand

The researchers only assessed the efficacy of BAX 855 prophylaxis and on-demand treatment in the phase 2/3 study.

Patients received a median dose of 44.6 IU/kg per prophylactic infusion. The mean reduction in dosing frequency from pre-study prophylaxis was 26.7%, and 70.4% of patients were able to reduce the frequency of dosing by 30% or more. This is roughly equivalent to at least 1 less prophylactic infusion per week.

Patients who received prophylaxis had a 90% reduction in ABR compared to those who received on-demand treatment. The median ABR was 1.9 in the prophylactic arm and 41.5 in the on-demand arm.

The ABRs for joint bleeds or spontaneous/unknown bleeds were both 0 in the prophylactic arm, compared to 38.1 and 21.6, respectively, in the on-demand treatment arm.

Patients who received on-demand treatment were given a median dose of 30.87 IU/kg per episode and 29.19 IU/kg for the maintenance of hemostasis.

Of the 518 bleeding episodes reported during the study, 95.9% were treated with 1 or 2 infusions of BAX 855. The mean number of infusions required to treat a bleeding episode was 1.2.

Patients with chronic myeloid leukemia (CML) treated with imatinib are much more likely to die from their comorbid conditions than from the leukemia, according to a report published in Blood.

During the past decade, CML has been transformed from a routinely fatal disease to a chronic condition controlled by regular drug therapy using imatinib and newer tyrosine kinase inhibitors. The influence of comorbidities on survival outcomes has not been studied until now, said Dr. Susanne Saussele of Heidelberg University, Mannheim (Germany), and her associates.

Wikimedia Commons/Difu Wu/Creative Commons license

They used data from a large German study of first-line imatinib therapy, focusing on 1,519 CML patients who were evaluable after a median follow-up of 68 months. Approximately 40% of these study participants had one or more of 511 evaluable comorbidities. The most common conditions relevant to CML and its treatment were diabetes, nonactive cancer other than CML, chronic pulmonary disease, renal insufficiency, MI, cerebrovascular disease, heart failure, and peripheral vascular disease.

Study participants were categorized by the number and severity of their comorbidities using the Charlson Comorbidity Index as CCI 2 (589 patients), CCI 3 or 4 (599 patients), CCI 5 or 6 (229 patients), or CCI 7 and above (102 patients), with higher levels indicating a greater burden of comorbidity. Overall 8-year survival probabilities directly correlated with CCI category, at 94% for CCI 2, 89% for CCI 3 or 4, 78% for CCI 5 or 6, and 46% for CCI 7 or above. In addition, CCI score was the most powerful predictor of overall survival, the researchers said (Blood 2015;126:42-9).

Comorbidities had no impact on the success of imatinib therapy. Even patients with multiple or severe comorbidities derived significant benefit from imatinib, and comorbidities had no negative effect on remission rates or disease progression. Taken together with comorbidities’ strong influence on mortality, this indicates that patients’ survival is determined more by their comorbidities than by CML itself, Dr. Saussele and her associates said.

Their findings also showed that overall survival alone is no longer an appropriate endpoint for assessing treatment efficacy in CML. Progression-free survival seems to be a more accurate measure of treatment effect, since it was not influenced by comorbidities in this study, they added.

Patients with chronic myeloid leukemia (CML) treated with imatinib are much more likely to die from their comorbid conditions than from the leukemia, according to a report published in Blood.

During the past decade, CML has been transformed from a routinely fatal disease to a chronic condition controlled by regular drug therapy using imatinib and newer tyrosine kinase inhibitors. The influence of comorbidities on survival outcomes has not been studied until now, said Dr. Susanne Saussele of Heidelberg University, Mannheim (Germany), and her associates.

Wikimedia Commons/Difu Wu/Creative Commons license

They used data from a large German study of first-line imatinib therapy, focusing on 1,519 CML patients who were evaluable after a median follow-up of 68 months. Approximately 40% of these study participants had one or more of 511 evaluable comorbidities. The most common conditions relevant to CML and its treatment were diabetes, nonactive cancer other than CML, chronic pulmonary disease, renal insufficiency, MI, cerebrovascular disease, heart failure, and peripheral vascular disease.

Study participants were categorized by the number and severity of their comorbidities using the Charlson Comorbidity Index as CCI 2 (589 patients), CCI 3 or 4 (599 patients), CCI 5 or 6 (229 patients), or CCI 7 and above (102 patients), with higher levels indicating a greater burden of comorbidity. Overall 8-year survival probabilities directly correlated with CCI category, at 94% for CCI 2, 89% for CCI 3 or 4, 78% for CCI 5 or 6, and 46% for CCI 7 or above. In addition, CCI score was the most powerful predictor of overall survival, the researchers said (Blood 2015;126:42-9).

Comorbidities had no impact on the success of imatinib therapy. Even patients with multiple or severe comorbidities derived significant benefit from imatinib, and comorbidities had no negative effect on remission rates or disease progression. Taken together with comorbidities’ strong influence on mortality, this indicates that patients’ survival is determined more by their comorbidities than by CML itself, Dr. Saussele and her associates said.

Their findings also showed that overall survival alone is no longer an appropriate endpoint for assessing treatment efficacy in CML. Progression-free survival seems to be a more accurate measure of treatment effect, since it was not influenced by comorbidities in this study, they added.

Patients with chronic myeloid leukemia (CML) treated with imatinib are much more likely to die from their comorbid conditions than from the leukemia, according to a report published in Blood.

During the past decade, CML has been transformed from a routinely fatal disease to a chronic condition controlled by regular drug therapy using imatinib and newer tyrosine kinase inhibitors. The influence of comorbidities on survival outcomes has not been studied until now, said Dr. Susanne Saussele of Heidelberg University, Mannheim (Germany), and her associates.

Wikimedia Commons/Difu Wu/Creative Commons license

They used data from a large German study of first-line imatinib therapy, focusing on 1,519 CML patients who were evaluable after a median follow-up of 68 months. Approximately 40% of these study participants had one or more of 511 evaluable comorbidities. The most common conditions relevant to CML and its treatment were diabetes, nonactive cancer other than CML, chronic pulmonary disease, renal insufficiency, MI, cerebrovascular disease, heart failure, and peripheral vascular disease.

Study participants were categorized by the number and severity of their comorbidities using the Charlson Comorbidity Index as CCI 2 (589 patients), CCI 3 or 4 (599 patients), CCI 5 or 6 (229 patients), or CCI 7 and above (102 patients), with higher levels indicating a greater burden of comorbidity. Overall 8-year survival probabilities directly correlated with CCI category, at 94% for CCI 2, 89% for CCI 3 or 4, 78% for CCI 5 or 6, and 46% for CCI 7 or above. In addition, CCI score was the most powerful predictor of overall survival, the researchers said (Blood 2015;126:42-9).

Comorbidities had no impact on the success of imatinib therapy. Even patients with multiple or severe comorbidities derived significant benefit from imatinib, and comorbidities had no negative effect on remission rates or disease progression. Taken together with comorbidities’ strong influence on mortality, this indicates that patients’ survival is determined more by their comorbidities than by CML itself, Dr. Saussele and her associates said.

Their findings also showed that overall survival alone is no longer an appropriate endpoint for assessing treatment efficacy in CML. Progression-free survival seems to be a more accurate measure of treatment effect, since it was not influenced by comorbidities in this study, they added.

Moderate thyroid hormone suppression therapy (THST) is associated with the best outcomes for patients with all stages of thyroid cancer, according to a prospective analysis of a multi-institutional registry published in the Journal of Clinical Endocrinology & Metabolism.

The researchers examined the outcomes of initial treatment for 4,941 patients with differentiated thyroid cancer (DTC), according to registry data from the National Thyroid Cancer Treatment Cooperative Study Group. The treatments included total/near total thyroidectomy (T/NTT), postoperative radioactive iodine-131 (¹³¹I), and THST. The median duration between treatment and follow-up for a patient was 6 years, with follow-up information available for all but 94 (1.9%) of the patients in the cohort.

Overall improvement was noted in stage III patients who received ¹³¹I (risk ratio, 0.66; P = .04) and stage IV patients who received both T/NTT and ¹³¹I (RR, 0.66; P = .049). In all stages, moderate THST was associated with significantly improved overall survival (RR stages I-IV: 0.13, 0.09, 0.13, and 0.33, respectively) and disease-free survival (DFS) (RR stages I-III: 0.52, 0.40, and 0.18, respectively); no additional survival benefit was achieved with more aggressive THST, even when distant metastatic disease was diagnosed during follow-up.

Lower initial stage and moderate THST were independent predictors of improved overall survival during follow-up years 1-3.

Consistent with previous research, this study also showed that T/NTT followed by ¹³¹I is associated with benefit in high-risk, but not low-risk patients.

“We report for the first time, in multivariate analysis of primary treatments for DTC, across all stages, only THST was associated with both improved stage-adjusted OS and DFS,” noted Dr. Aubrey A. Carhill and his colleagues.

“This analysis of the larger, more mature registry database extends and refines earlier observations regarding the impact of initial therapies on patient outcomes and further justifies the need for prospective, long-term, controlled studies,” the researchers noted.

Read the full study in the Journal of Clinical Endocrinology & Metabolism (doi:10.1210/JC.2015-1346).

[email protected]

Moderate thyroid hormone suppression therapy (THST) is associated with the best outcomes for patients with all stages of thyroid cancer, according to a prospective analysis of a multi-institutional registry published in the Journal of Clinical Endocrinology & Metabolism.

The researchers examined the outcomes of initial treatment for 4,941 patients with differentiated thyroid cancer (DTC), according to registry data from the National Thyroid Cancer Treatment Cooperative Study Group. The treatments included total/near total thyroidectomy (T/NTT), postoperative radioactive iodine-131 (¹³¹I), and THST. The median duration between treatment and follow-up for a patient was 6 years, with follow-up information available for all but 94 (1.9%) of the patients in the cohort.

Overall improvement was noted in stage III patients who received ¹³¹I (risk ratio, 0.66; P = .04) and stage IV patients who received both T/NTT and ¹³¹I (RR, 0.66; P = .049). In all stages, moderate THST was associated with significantly improved overall survival (RR stages I-IV: 0.13, 0.09, 0.13, and 0.33, respectively) and disease-free survival (DFS) (RR stages I-III: 0.52, 0.40, and 0.18, respectively); no additional survival benefit was achieved with more aggressive THST, even when distant metastatic disease was diagnosed during follow-up.

Lower initial stage and moderate THST were independent predictors of improved overall survival during follow-up years 1-3.

Consistent with previous research, this study also showed that T/NTT followed by ¹³¹I is associated with benefit in high-risk, but not low-risk patients.

“We report for the first time, in multivariate analysis of primary treatments for DTC, across all stages, only THST was associated with both improved stage-adjusted OS and DFS,” noted Dr. Aubrey A. Carhill and his colleagues.

“This analysis of the larger, more mature registry database extends and refines earlier observations regarding the impact of initial therapies on patient outcomes and further justifies the need for prospective, long-term, controlled studies,” the researchers noted.

Read the full study in the Journal of Clinical Endocrinology & Metabolism (doi:10.1210/JC.2015-1346).

[email protected]

Moderate thyroid hormone suppression therapy (THST) is associated with the best outcomes for patients with all stages of thyroid cancer, according to a prospective analysis of a multi-institutional registry published in the Journal of Clinical Endocrinology & Metabolism.

The researchers examined the outcomes of initial treatment for 4,941 patients with differentiated thyroid cancer (DTC), according to registry data from the National Thyroid Cancer Treatment Cooperative Study Group. The treatments included total/near total thyroidectomy (T/NTT), postoperative radioactive iodine-131 (¹³¹I), and THST. The median duration between treatment and follow-up for a patient was 6 years, with follow-up information available for all but 94 (1.9%) of the patients in the cohort.

Overall improvement was noted in stage III patients who received ¹³¹I (risk ratio, 0.66; P = .04) and stage IV patients who received both T/NTT and ¹³¹I (RR, 0.66; P = .049). In all stages, moderate THST was associated with significantly improved overall survival (RR stages I-IV: 0.13, 0.09, 0.13, and 0.33, respectively) and disease-free survival (DFS) (RR stages I-III: 0.52, 0.40, and 0.18, respectively); no additional survival benefit was achieved with more aggressive THST, even when distant metastatic disease was diagnosed during follow-up.

Lower initial stage and moderate THST were independent predictors of improved overall survival during follow-up years 1-3.

Consistent with previous research, this study also showed that T/NTT followed by ¹³¹I is associated with benefit in high-risk, but not low-risk patients.

“We report for the first time, in multivariate analysis of primary treatments for DTC, across all stages, only THST was associated with both improved stage-adjusted OS and DFS,” noted Dr. Aubrey A. Carhill and his colleagues.

“This analysis of the larger, more mature registry database extends and refines earlier observations regarding the impact of initial therapies on patient outcomes and further justifies the need for prospective, long-term, controlled studies,” the researchers noted.

Read the full study in the Journal of Clinical Endocrinology & Metabolism (doi:10.1210/JC.2015-1346).

[email protected]

Duchenne muscular dystrophy (DMD), an X-linked condition, is the most common muscular dystrophy in children and affects families of all ethnicities. Incidence is about 1 in 3,500 boys. Approximately two-thirds of clinically diagnosed cases of DMD are attributable to a carrier mother, who is likely unaware that she is a carrier. In addition to providing information about reproductive risks, carrier screening can identify women who are, themselves, at risk of health effects caused by defects in the DMD gene.

This supplement examines the latest crucial advances in DMD carrier screening.

Click here to download the PDF.

To view an exclusive video on the pivotal findings discussed in this supplement, click here.

Duchenne muscular dystrophy (DMD), an X-linked condition, is the most common muscular dystrophy in children and affects families of all ethnicities. Incidence is about 1 in 3,500 boys. Approximately two-thirds of clinically diagnosed cases of DMD are attributable to a carrier mother, who is likely unaware that she is a carrier. In addition to providing information about reproductive risks, carrier screening can identify women who are, themselves, at risk of health effects caused by defects in the DMD gene.

This supplement examines the latest crucial advances in DMD carrier screening.

Click here to download the PDF.

To view an exclusive video on the pivotal findings discussed in this supplement, click here.

Duchenne muscular dystrophy (DMD), an X-linked condition, is the most common muscular dystrophy in children and affects families of all ethnicities. Incidence is about 1 in 3,500 boys. Approximately two-thirds of clinically diagnosed cases of DMD are attributable to a carrier mother, who is likely unaware that she is a carrier. In addition to providing information about reproductive risks, carrier screening can identify women who are, themselves, at risk of health effects caused by defects in the DMD gene.

This supplement examines the latest crucial advances in DMD carrier screening.

Click here to download the PDF.

To view an exclusive video on the pivotal findings discussed in this supplement, click here.

Half of moderate to severe traumatic brain injury patients had markedly impaired corpus callosum (CC) functioning and structural integrity that is associated with poor neurocognitive functioning, according to a study of children aged 8-19 years.

The researchers used high angular resolution diffusion-weighted imaging to determine the structural integrities of the CC in 32 children who had suffered a traumatic brain injury (TBI) and of the CC in 31 healthy children. Patients in the experimental group had suffered from a moderate to severe TBI 1-5 months prior to the study. The researchers assessed CC function through interhemispheric transfer time (IHTT) – the time required to transfer stimulus-locked neural activity between the left and right brain hemispheres. Each participant’s IHTT was calculated from recording electroencephalography, while he or she completed a computerized, pattern-matching task with bilateral field advantage.

Half of the TBI patients had significantly slower IHTTs than did the control group. The IHTTs of this so-called IHTT-slow TBI group deviated by at least 1.5 standard deviations from data for the healthy control group.

The IHTT-slow TBI group also demonstrated lower CC integrity and poorer neurocognitive functioning than did both the control group and the remaining members of the experimental group. Lower fractional anisotropy (FA) – a common sign of impaired white matter (WM) – and slower IHTTs also predicted poor neurocognitive function.

“When we compared the IHTT-slow TBI group to the healthy control group, we found significant differences in callosal WM integrity, as well as the integrity of the association and projection tract systems tested. Lower FA and higher mean diffusivity (MD) in the IHTT-slow group suggests myelin disruption,” noted Emily L Dennis of the University of Southern California, Marina del Rey, and her colleagues. “When we compared the IHTT-normal TBI group to the healthy control group, we found only a few areas where the TBI group had significantly lower FA and no significant differences in MD [mean diffusivity].”

Read the full study in the Journal of Neuroscience (doi:10.1523/JNEUROSCI.1595-15.2015).

[email protected]

Half of moderate to severe traumatic brain injury patients had markedly impaired corpus callosum (CC) functioning and structural integrity that is associated with poor neurocognitive functioning, according to a study of children aged 8-19 years.

The researchers used high angular resolution diffusion-weighted imaging to determine the structural integrities of the CC in 32 children who had suffered a traumatic brain injury (TBI) and of the CC in 31 healthy children. Patients in the experimental group had suffered from a moderate to severe TBI 1-5 months prior to the study. The researchers assessed CC function through interhemispheric transfer time (IHTT) – the time required to transfer stimulus-locked neural activity between the left and right brain hemispheres. Each participant’s IHTT was calculated from recording electroencephalography, while he or she completed a computerized, pattern-matching task with bilateral field advantage.

Half of the TBI patients had significantly slower IHTTs than did the control group. The IHTTs of this so-called IHTT-slow TBI group deviated by at least 1.5 standard deviations from data for the healthy control group.

The IHTT-slow TBI group also demonstrated lower CC integrity and poorer neurocognitive functioning than did both the control group and the remaining members of the experimental group. Lower fractional anisotropy (FA) – a common sign of impaired white matter (WM) – and slower IHTTs also predicted poor neurocognitive function.

“When we compared the IHTT-slow TBI group to the healthy control group, we found significant differences in callosal WM integrity, as well as the integrity of the association and projection tract systems tested. Lower FA and higher mean diffusivity (MD) in the IHTT-slow group suggests myelin disruption,” noted Emily L Dennis of the University of Southern California, Marina del Rey, and her colleagues. “When we compared the IHTT-normal TBI group to the healthy control group, we found only a few areas where the TBI group had significantly lower FA and no significant differences in MD [mean diffusivity].”

Read the full study in the Journal of Neuroscience (doi:10.1523/JNEUROSCI.1595-15.2015).

[email protected]

Half of moderate to severe traumatic brain injury patients had markedly impaired corpus callosum (CC) functioning and structural integrity that is associated with poor neurocognitive functioning, according to a study of children aged 8-19 years.

The researchers used high angular resolution diffusion-weighted imaging to determine the structural integrities of the CC in 32 children who had suffered a traumatic brain injury (TBI) and of the CC in 31 healthy children. Patients in the experimental group had suffered from a moderate to severe TBI 1-5 months prior to the study. The researchers assessed CC function through interhemispheric transfer time (IHTT) – the time required to transfer stimulus-locked neural activity between the left and right brain hemispheres. Each participant’s IHTT was calculated from recording electroencephalography, while he or she completed a computerized, pattern-matching task with bilateral field advantage.

Half of the TBI patients had significantly slower IHTTs than did the control group. The IHTTs of this so-called IHTT-slow TBI group deviated by at least 1.5 standard deviations from data for the healthy control group.

The IHTT-slow TBI group also demonstrated lower CC integrity and poorer neurocognitive functioning than did both the control group and the remaining members of the experimental group. Lower fractional anisotropy (FA) – a common sign of impaired white matter (WM) – and slower IHTTs also predicted poor neurocognitive function.

“When we compared the IHTT-slow TBI group to the healthy control group, we found significant differences in callosal WM integrity, as well as the integrity of the association and projection tract systems tested. Lower FA and higher mean diffusivity (MD) in the IHTT-slow group suggests myelin disruption,” noted Emily L Dennis of the University of Southern California, Marina del Rey, and her colleagues. “When we compared the IHTT-normal TBI group to the healthy control group, we found only a few areas where the TBI group had significantly lower FA and no significant differences in MD [mean diffusivity].”

Read the full study in the Journal of Neuroscience (doi:10.1523/JNEUROSCI.1595-15.2015).

[email protected]

At the insistence of his wife, a 39-year-old man presents to dermatology for evaluation of a lesion on his neck that manifested three years ago. As the lesion has grown, darkened, and become more irregular in outline, she has urged him to have it checked. Her efforts finally succeeded when several of his coworkers also commented on it.

The patient has a history of sun exposure but says he tolerates it well and tans easily. He is otherwise healthy.

EXAMINATION
The irregularly pigmented and bordered dark brown macule, located on the lateral aspect of the left side of his neck,  measures about 2 cm in its greatest dimension. The rest of his neck shows definite signs of chronic UV overexposure, in the form of poikilodermatous changes.

Dermatoscopic examination of the lesion shows focal areas of pigment streaming and blue veiling—both indicative of melanoma. In light of these findings and in the context of his heavily sun-damaged skin, the patient is scheduled for excision. This is performed one week later; the lesion is removed with 5-mm margins, producing a curved, elliptiform defect to match local skin lines, with a two-layer closure.

What is the diagnosis?

DISCUSSION
The pathology report showed the lesion to be an early lentigo maligna (LM). Most authorities in the field do not consider this a true melanoma, although it is probably best considered a type of melanoma in situ. LM definitely involves cellular atypia, but at a very superficial level. Only a tiny fraction of LMs ever become invasive—and only after several years of being left in place.

LM isn’t always as obvious as this patient’s lesion is. It can be brown, red, or even bluish and can blend into surrounding mottled skin lesions (eg, solar lentigines, seborrheic keratoses or actinic keratosis). The key to diagnosis is to observe for change in size and/or color, especially on sun-exposed areas of skin in older, sun-damaged patients.

In this case, the decision to excise the lesion was made easier by its size and location. Larger lesions of uncertain dimensions may be assessed with multiple punch biopsies.

Once LM is diagnosed, the problem becomes obtaining adequate margins surgically, given the often ill-defined dimensions of the lesion. Failure rates, even when Mohs surgery is performed, are all too high. Surgery has therefore been combined with the application of immune-enhancing creams (eg, imiquimod), a method that shows promise but yields conflicting results in studies.

Since many LMs appear on truly elderly patients, and since their evolution to invasive status is so slow, they don’t command the same urgency as a truly invasive melanoma. Clinically, however, this patient’s lesion met the criteria by which we judge potentially malignant lesions: asymmetry, irregular borders, odd color, and large size. It could easily have been an invasive melanoma, either at the time or in future. Finding and identifying it not only delivered peace of mind but also provided a warning that the patient had some serious sun damage—and therefore the potential to develop other cutaneous malignancies.

Fortunately, a whole-body check revealed no other worrisome lesions. The patient has, however, been scheduled for twice-yearly skin checks. He also received education on the recognition of melanoma.

TAKE-HOME LEARNING POINTS
• The prognosis for a melanoma is determined by numerous factors, most notably the vertical thickness of the lesion, as measured under the microscope by the examining pathologist.

• The lentigo maligna lesion, as seen in this case, can be so thin and superficial that some experts don’t consider it a true melanoma.

• Nonetheless, the gross appearance of such lesions typifies the main diagnostic features (ABCDs) of melanoma: Asymmetry, odd Borders, odd Colors, and Diameter (large size).

• The finding of an LM means the patient has increased risk for invasive melanoma in the future.

At the insistence of his wife, a 39-year-old man presents to dermatology for evaluation of a lesion on his neck that manifested three years ago. As the lesion has grown, darkened, and become more irregular in outline, she has urged him to have it checked. Her efforts finally succeeded when several of his coworkers also commented on it.

The patient has a history of sun exposure but says he tolerates it well and tans easily. He is otherwise healthy.

EXAMINATION
The irregularly pigmented and bordered dark brown macule, located on the lateral aspect of the left side of his neck,  measures about 2 cm in its greatest dimension. The rest of his neck shows definite signs of chronic UV overexposure, in the form of poikilodermatous changes.

Dermatoscopic examination of the lesion shows focal areas of pigment streaming and blue veiling—both indicative of melanoma. In light of these findings and in the context of his heavily sun-damaged skin, the patient is scheduled for excision. This is performed one week later; the lesion is removed with 5-mm margins, producing a curved, elliptiform defect to match local skin lines, with a two-layer closure.

What is the diagnosis?

DISCUSSION
The pathology report showed the lesion to be an early lentigo maligna (LM). Most authorities in the field do not consider this a true melanoma, although it is probably best considered a type of melanoma in situ. LM definitely involves cellular atypia, but at a very superficial level. Only a tiny fraction of LMs ever become invasive—and only after several years of being left in place.

LM isn’t always as obvious as this patient’s lesion is. It can be brown, red, or even bluish and can blend into surrounding mottled skin lesions (eg, solar lentigines, seborrheic keratoses or actinic keratosis). The key to diagnosis is to observe for change in size and/or color, especially on sun-exposed areas of skin in older, sun-damaged patients.

In this case, the decision to excise the lesion was made easier by its size and location. Larger lesions of uncertain dimensions may be assessed with multiple punch biopsies.

Once LM is diagnosed, the problem becomes obtaining adequate margins surgically, given the often ill-defined dimensions of the lesion. Failure rates, even when Mohs surgery is performed, are all too high. Surgery has therefore been combined with the application of immune-enhancing creams (eg, imiquimod), a method that shows promise but yields conflicting results in studies.

Since many LMs appear on truly elderly patients, and since their evolution to invasive status is so slow, they don’t command the same urgency as a truly invasive melanoma. Clinically, however, this patient’s lesion met the criteria by which we judge potentially malignant lesions: asymmetry, irregular borders, odd color, and large size. It could easily have been an invasive melanoma, either at the time or in future. Finding and identifying it not only delivered peace of mind but also provided a warning that the patient had some serious sun damage—and therefore the potential to develop other cutaneous malignancies.

Fortunately, a whole-body check revealed no other worrisome lesions. The patient has, however, been scheduled for twice-yearly skin checks. He also received education on the recognition of melanoma.

TAKE-HOME LEARNING POINTS
• The prognosis for a melanoma is determined by numerous factors, most notably the vertical thickness of the lesion, as measured under the microscope by the examining pathologist.

• The lentigo maligna lesion, as seen in this case, can be so thin and superficial that some experts don’t consider it a true melanoma.

• Nonetheless, the gross appearance of such lesions typifies the main diagnostic features (ABCDs) of melanoma: Asymmetry, odd Borders, odd Colors, and Diameter (large size).

• The finding of an LM means the patient has increased risk for invasive melanoma in the future.

At the insistence of his wife, a 39-year-old man presents to dermatology for evaluation of a lesion on his neck that manifested three years ago. As the lesion has grown, darkened, and become more irregular in outline, she has urged him to have it checked. Her efforts finally succeeded when several of his coworkers also commented on it.

The patient has a history of sun exposure but says he tolerates it well and tans easily. He is otherwise healthy.

EXAMINATION
The irregularly pigmented and bordered dark brown macule, located on the lateral aspect of the left side of his neck,  measures about 2 cm in its greatest dimension. The rest of his neck shows definite signs of chronic UV overexposure, in the form of poikilodermatous changes.

Dermatoscopic examination of the lesion shows focal areas of pigment streaming and blue veiling—both indicative of melanoma. In light of these findings and in the context of his heavily sun-damaged skin, the patient is scheduled for excision. This is performed one week later; the lesion is removed with 5-mm margins, producing a curved, elliptiform defect to match local skin lines, with a two-layer closure.

What is the diagnosis?

DISCUSSION
The pathology report showed the lesion to be an early lentigo maligna (LM). Most authorities in the field do not consider this a true melanoma, although it is probably best considered a type of melanoma in situ. LM definitely involves cellular atypia, but at a very superficial level. Only a tiny fraction of LMs ever become invasive—and only after several years of being left in place.

LM isn’t always as obvious as this patient’s lesion is. It can be brown, red, or even bluish and can blend into surrounding mottled skin lesions (eg, solar lentigines, seborrheic keratoses or actinic keratosis). The key to diagnosis is to observe for change in size and/or color, especially on sun-exposed areas of skin in older, sun-damaged patients.

In this case, the decision to excise the lesion was made easier by its size and location. Larger lesions of uncertain dimensions may be assessed with multiple punch biopsies.

Once LM is diagnosed, the problem becomes obtaining adequate margins surgically, given the often ill-defined dimensions of the lesion. Failure rates, even when Mohs surgery is performed, are all too high. Surgery has therefore been combined with the application of immune-enhancing creams (eg, imiquimod), a method that shows promise but yields conflicting results in studies.

Since many LMs appear on truly elderly patients, and since their evolution to invasive status is so slow, they don’t command the same urgency as a truly invasive melanoma. Clinically, however, this patient’s lesion met the criteria by which we judge potentially malignant lesions: asymmetry, irregular borders, odd color, and large size. It could easily have been an invasive melanoma, either at the time or in future. Finding and identifying it not only delivered peace of mind but also provided a warning that the patient had some serious sun damage—and therefore the potential to develop other cutaneous malignancies.

Fortunately, a whole-body check revealed no other worrisome lesions. The patient has, however, been scheduled for twice-yearly skin checks. He also received education on the recognition of melanoma.

TAKE-HOME LEARNING POINTS
• The prognosis for a melanoma is determined by numerous factors, most notably the vertical thickness of the lesion, as measured under the microscope by the examining pathologist.

• The lentigo maligna lesion, as seen in this case, can be so thin and superficial that some experts don’t consider it a true melanoma.

• Nonetheless, the gross appearance of such lesions typifies the main diagnostic features (ABCDs) of melanoma: Asymmetry, odd Borders, odd Colors, and Diameter (large size).

• The finding of an LM means the patient has increased risk for invasive melanoma in the future.