ATLANTA – More than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta), often called axi-cel, had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion, according to investigators in the ZUMA-1 trial.

Neil Osterweil/Frontline Medical News

Updated combined phase 1 and phase 2 results in 108 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) showed an objective response rate (ORR) of 82%, including 58% complete responses, after a median follow-up of 15.4 months, reported Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“Axi-cel is highly effective in patients with large B-cell lymphoma who otherwise have no curative treatment options,” he said in a briefing at the annual meeting of the American Society of Hematology, prior to his presentation of the data in an oral session.

The trial results were also published simultaneously in the New England Journal of Medicine.As previously reported, in the multicenter phase 2 ZUMA-1 trial, 111 patients with treatment refractory DLBCL, PMBCL, or TFL were enrolled and treated with axi-cel at a target dose of 2 x 10⁶ cells/kg, following a conditioning regimen with low-dose cyclophosphamide and fludarabine.

The median patient age was 58 years. Patients had stage III or IV disease, 48% had International Prognostic Index scores of 3-4, 76% had disease that was refractory to third-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant

Axi-cel was successfully manufactured with sufficient cells for transfusion in all but one of the 111 patients, and 101 patients eventually received infusions in phase 2 (modified intention-to-treat population). The average turnaround time from apheresis to the clinical site was 17 days.

Dr. Neelapu also presented data on seven patients enrolled in phase 1; the data were combined with the phase 2 results for an updated analysis of those patients who had at least 1 year of follow-up.

The phase 2 trial met its primary endpoint at the time of the primary analysis, with an 82% ORR, consisting of 54% complete responses and 28% partial responses at a median follow-up of 8.7 months.

In the updated analysis, the ORR and respective remission rates were 82%, 58%, and 34%, at a median of 15.4 months follow-up.

The median duration of response in the updated analysis was 11.1 months. The median duration of complete responses had not been reached at the time of data cutoff in August 2017. The median duration of partial responses was 1.9 months.

At the 15.4-month mark, 42% of patients remained free of disease progression, and 56% were alive, with the median overall survival not yet reached.

The treatment had generally acceptable toxicities, with only 13% of patients in phase 2 experiencing grade 3 or greater cytokine release syndrome (CRS), although one patient with CRS died from hemophagocytic lymphohistiocytosis, and one with CRS died from cardiac arrest. Grade 3 or greater neurologic events occurred in 28% of patients, and included encephalopathy, confusional state, aphasia, and somnolence.

The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.

Since the primary analysis with at least 6 months of follow-up, there have been no new axi-cel–related cases of CRS, neurologic events, or deaths.

Dr. Neelapu also presented safety data on serious adverse events occurring more than 6 months after therapy in 10 patients who developed symptoms after the data cutoff.

Grade 3 events in these patients included lung infection, recurrent upper respiratory viral infection, and rotavirus infection, pneumonias, atrial fibrillation with rapid ventricular response, lung infection, febrile neutropenia, and influenza B infection. One patient had grade 4 sepsis.

In an editorial accompanying the study in the New England Journal of Medicine, Eric Tran, PhD, and Walter J. Urba, MD, PhD, from the Earle A. Chiles Research Institute and the Providence Portland (Ore.) Medical Center, and Dan L. Longo, MD, deputy editor of the journal, praised ZUMA-1 as “a landmark study because it involved 22 institutions and showed that a personalized gene-engineered T-cell product could be rapidly generated at a centralized cell-manufacturing facility and safely administered to patients at transplantation-capable medical centers.”

They noted, however, that about half of all patients with relapsed or refractory large B-cell lymphomas will not have durable responses to CAR T-cell therapy directed against CD19, and that new strategies will be needed to improve responses (N Engl J Med. 2017 Dec 10; doi: 10.1056/NEJMe1714680).

In the question and answer session at the end of the briefing, Dr. Neelapu said the preliminary observations of mechanisms of relapse or disease progression in some patients may be related to the loss of the CD19 antigen, which occurs in about one-third of patients who experience relapse, and to high expression of the programmed death ligand-1, which can potentially inhibit CAR-T cell function. A clinical trial is currently underway to evaluate potential strategies for improving response rates to CAR-T therapies, he said.

ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.

SOURCE: Neelapu S et al. ASH 2017 Abstract 578.

ATLANTA – More than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta), often called axi-cel, had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion, according to investigators in the ZUMA-1 trial.

Neil Osterweil/Frontline Medical News

Updated combined phase 1 and phase 2 results in 108 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) showed an objective response rate (ORR) of 82%, including 58% complete responses, after a median follow-up of 15.4 months, reported Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“Axi-cel is highly effective in patients with large B-cell lymphoma who otherwise have no curative treatment options,” he said in a briefing at the annual meeting of the American Society of Hematology, prior to his presentation of the data in an oral session.

The trial results were also published simultaneously in the New England Journal of Medicine.As previously reported, in the multicenter phase 2 ZUMA-1 trial, 111 patients with treatment refractory DLBCL, PMBCL, or TFL were enrolled and treated with axi-cel at a target dose of 2 x 10⁶ cells/kg, following a conditioning regimen with low-dose cyclophosphamide and fludarabine.

The median patient age was 58 years. Patients had stage III or IV disease, 48% had International Prognostic Index scores of 3-4, 76% had disease that was refractory to third-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant

Axi-cel was successfully manufactured with sufficient cells for transfusion in all but one of the 111 patients, and 101 patients eventually received infusions in phase 2 (modified intention-to-treat population). The average turnaround time from apheresis to the clinical site was 17 days.

Dr. Neelapu also presented data on seven patients enrolled in phase 1; the data were combined with the phase 2 results for an updated analysis of those patients who had at least 1 year of follow-up.

The phase 2 trial met its primary endpoint at the time of the primary analysis, with an 82% ORR, consisting of 54% complete responses and 28% partial responses at a median follow-up of 8.7 months.

In the updated analysis, the ORR and respective remission rates were 82%, 58%, and 34%, at a median of 15.4 months follow-up.

The median duration of response in the updated analysis was 11.1 months. The median duration of complete responses had not been reached at the time of data cutoff in August 2017. The median duration of partial responses was 1.9 months.

At the 15.4-month mark, 42% of patients remained free of disease progression, and 56% were alive, with the median overall survival not yet reached.

The treatment had generally acceptable toxicities, with only 13% of patients in phase 2 experiencing grade 3 or greater cytokine release syndrome (CRS), although one patient with CRS died from hemophagocytic lymphohistiocytosis, and one with CRS died from cardiac arrest. Grade 3 or greater neurologic events occurred in 28% of patients, and included encephalopathy, confusional state, aphasia, and somnolence.

The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.

Since the primary analysis with at least 6 months of follow-up, there have been no new axi-cel–related cases of CRS, neurologic events, or deaths.

Dr. Neelapu also presented safety data on serious adverse events occurring more than 6 months after therapy in 10 patients who developed symptoms after the data cutoff.

Grade 3 events in these patients included lung infection, recurrent upper respiratory viral infection, and rotavirus infection, pneumonias, atrial fibrillation with rapid ventricular response, lung infection, febrile neutropenia, and influenza B infection. One patient had grade 4 sepsis.

In an editorial accompanying the study in the New England Journal of Medicine, Eric Tran, PhD, and Walter J. Urba, MD, PhD, from the Earle A. Chiles Research Institute and the Providence Portland (Ore.) Medical Center, and Dan L. Longo, MD, deputy editor of the journal, praised ZUMA-1 as “a landmark study because it involved 22 institutions and showed that a personalized gene-engineered T-cell product could be rapidly generated at a centralized cell-manufacturing facility and safely administered to patients at transplantation-capable medical centers.”

They noted, however, that about half of all patients with relapsed or refractory large B-cell lymphomas will not have durable responses to CAR T-cell therapy directed against CD19, and that new strategies will be needed to improve responses (N Engl J Med. 2017 Dec 10; doi: 10.1056/NEJMe1714680).

In the question and answer session at the end of the briefing, Dr. Neelapu said the preliminary observations of mechanisms of relapse or disease progression in some patients may be related to the loss of the CD19 antigen, which occurs in about one-third of patients who experience relapse, and to high expression of the programmed death ligand-1, which can potentially inhibit CAR-T cell function. A clinical trial is currently underway to evaluate potential strategies for improving response rates to CAR-T therapies, he said.

ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.

SOURCE: Neelapu S et al. ASH 2017 Abstract 578.

ATLANTA – More than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta), often called axi-cel, had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion, according to investigators in the ZUMA-1 trial.

Neil Osterweil/Frontline Medical News

Updated combined phase 1 and phase 2 results in 108 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) showed an objective response rate (ORR) of 82%, including 58% complete responses, after a median follow-up of 15.4 months, reported Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“Axi-cel is highly effective in patients with large B-cell lymphoma who otherwise have no curative treatment options,” he said in a briefing at the annual meeting of the American Society of Hematology, prior to his presentation of the data in an oral session.

The trial results were also published simultaneously in the New England Journal of Medicine.As previously reported, in the multicenter phase 2 ZUMA-1 trial, 111 patients with treatment refractory DLBCL, PMBCL, or TFL were enrolled and treated with axi-cel at a target dose of 2 x 10⁶ cells/kg, following a conditioning regimen with low-dose cyclophosphamide and fludarabine.

The median patient age was 58 years. Patients had stage III or IV disease, 48% had International Prognostic Index scores of 3-4, 76% had disease that was refractory to third-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant

Axi-cel was successfully manufactured with sufficient cells for transfusion in all but one of the 111 patients, and 101 patients eventually received infusions in phase 2 (modified intention-to-treat population). The average turnaround time from apheresis to the clinical site was 17 days.

Dr. Neelapu also presented data on seven patients enrolled in phase 1; the data were combined with the phase 2 results for an updated analysis of those patients who had at least 1 year of follow-up.

The phase 2 trial met its primary endpoint at the time of the primary analysis, with an 82% ORR, consisting of 54% complete responses and 28% partial responses at a median follow-up of 8.7 months.

In the updated analysis, the ORR and respective remission rates were 82%, 58%, and 34%, at a median of 15.4 months follow-up.

The median duration of response in the updated analysis was 11.1 months. The median duration of complete responses had not been reached at the time of data cutoff in August 2017. The median duration of partial responses was 1.9 months.

At the 15.4-month mark, 42% of patients remained free of disease progression, and 56% were alive, with the median overall survival not yet reached.

The treatment had generally acceptable toxicities, with only 13% of patients in phase 2 experiencing grade 3 or greater cytokine release syndrome (CRS), although one patient with CRS died from hemophagocytic lymphohistiocytosis, and one with CRS died from cardiac arrest. Grade 3 or greater neurologic events occurred in 28% of patients, and included encephalopathy, confusional state, aphasia, and somnolence.

The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.

Since the primary analysis with at least 6 months of follow-up, there have been no new axi-cel–related cases of CRS, neurologic events, or deaths.

Dr. Neelapu also presented safety data on serious adverse events occurring more than 6 months after therapy in 10 patients who developed symptoms after the data cutoff.

Grade 3 events in these patients included lung infection, recurrent upper respiratory viral infection, and rotavirus infection, pneumonias, atrial fibrillation with rapid ventricular response, lung infection, febrile neutropenia, and influenza B infection. One patient had grade 4 sepsis.

In an editorial accompanying the study in the New England Journal of Medicine, Eric Tran, PhD, and Walter J. Urba, MD, PhD, from the Earle A. Chiles Research Institute and the Providence Portland (Ore.) Medical Center, and Dan L. Longo, MD, deputy editor of the journal, praised ZUMA-1 as “a landmark study because it involved 22 institutions and showed that a personalized gene-engineered T-cell product could be rapidly generated at a centralized cell-manufacturing facility and safely administered to patients at transplantation-capable medical centers.”

They noted, however, that about half of all patients with relapsed or refractory large B-cell lymphomas will not have durable responses to CAR T-cell therapy directed against CD19, and that new strategies will be needed to improve responses (N Engl J Med. 2017 Dec 10; doi: 10.1056/NEJMe1714680).

In the question and answer session at the end of the briefing, Dr. Neelapu said the preliminary observations of mechanisms of relapse or disease progression in some patients may be related to the loss of the CD19 antigen, which occurs in about one-third of patients who experience relapse, and to high expression of the programmed death ligand-1, which can potentially inhibit CAR-T cell function. A clinical trial is currently underway to evaluate potential strategies for improving response rates to CAR-T therapies, he said.

ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.

SOURCE: Neelapu S et al. ASH 2017 Abstract 578.

ATLANTA – An expert panel convened by the American Society of Hematology will recommend against routine venous thromboembolism (VTE) prophylaxis with low-molecular-weight heparin, except in patients deemed high risk, the panel chair told attendees at the group’s annual meeting.

The recommendations will be posted for public comment in early 2018 and are expected to be finalized and published later in the year.

The panel found strong evidence to recommend against prophylaxis in cancer patients at low risk of VTE, said Gary H. Lyman, MD, of the Fred Hutchinson Cancer Research Center and the University of Washington, both in Seattle.

For cancer patients at high risk of VTE, the panel will make a conditional recommendation – based on weaker evidence – in favor of low-molecular-weight thromboprophylaxis (LMWH) “with a caveat that patients should have no major bleeding risk or other contraindication to anticoagulation,” Dr. Lyman said.

The panel also found weaker evidence to support a conditional recommendation against routine prophylaxis in patients at intermediate risk of VTE, based on results from a systematic review.

These recommendations, which were described during a special education session at the annual meeting of the American Society of Hematology, are just one piece of a larger effort by ASH to develop evidence-based guidelines on VTE management. More than 100 thrombosis experts have reviewed evidence and drafted more than 200 recommendations on diagnosis, prevention, and treatment of VTE, according to ASH.

The cancer-specific recommendations described by Dr. Lyman are based in part on a meta-analysis of 17 randomized controlled trials of cancer patients receiving LMWH thromboprophylaxis that were published between 2008 and 2017. Across cancer types and settings, LMWH prophylaxis in these trials was associated with a reduced risk of VTE and an increased risk of bleeding, Dr. Lyman said.

For all cancer types, relative risk (RR) of VTE was 0.55 (95% confidence interval, 0.46-0.65), with an absolute risk reduction of just 2.7% “because of the low baseline risk of VTE in this setting,” Dr. Lyman said.

However, the baseline risk increased for certain cancer types, including lung cancer, which had a similar relative risk of 0.53 (95% CI, 0.41-0.69) but an absolute risk reduction of 4.3%, according to data Dr. Lyman presented. Likewise, pancreatic cancer was associated with a relative risk of 0.43 (95% CI, 0.25-0.73) but an absolute risk reduction of 10.1%.

Major bleeding across all trials was significantly increased (RR 1.40; 95% CI, 1.01-1.92), but the presented data show that, in absolute terms, the increase was just 0.7% overall and similarly, 0.7% and 0.9% for lung and pancreatic cancer, respectively.

However, VTE risk depends on more than the site of the cancer, Dr. Lyman noted. In their deliberations, the panel considered the validated Khorana Risk Score, which incorporates factors such as body mass index, platelet count, leukocyte count, and hemoglobin level.

Specific analysis of high-risk patients suggested a pronounced risk reduction associated with LMWH prophylaxis, according to Dr. Lyman, who noted that a patient-level analysis including nearly 8,000 patients from 13 randomized, controlled trials showed a relative risk of 0.58, with VTE events seen in 4.0% patients in the LMWH group versus 7.0% of controls.

The forthcoming ASH guidelines also will address other aspects of cancer-associated VTE, according to Dr. Lyman, including initial treatment, secondary prophylaxis, perioperative prophylaxis, and prophylaxis or treatment in patients with a central venous catheter.

“The risk of venous thromboembolism in patients with cancer is well recognized, and that risk is especially notable in patients receiving cancer treatment,” Dr. Lyman said.

Dr. Lyman reported having no relevant financial disclosures.

hematologynews@frontlinemedcom.com

ATLANTA – An expert panel convened by the American Society of Hematology will recommend against routine venous thromboembolism (VTE) prophylaxis with low-molecular-weight heparin, except in patients deemed high risk, the panel chair told attendees at the group’s annual meeting.

The recommendations will be posted for public comment in early 2018 and are expected to be finalized and published later in the year.

The panel found strong evidence to recommend against prophylaxis in cancer patients at low risk of VTE, said Gary H. Lyman, MD, of the Fred Hutchinson Cancer Research Center and the University of Washington, both in Seattle.

For cancer patients at high risk of VTE, the panel will make a conditional recommendation – based on weaker evidence – in favor of low-molecular-weight thromboprophylaxis (LMWH) “with a caveat that patients should have no major bleeding risk or other contraindication to anticoagulation,” Dr. Lyman said.

The panel also found weaker evidence to support a conditional recommendation against routine prophylaxis in patients at intermediate risk of VTE, based on results from a systematic review.

These recommendations, which were described during a special education session at the annual meeting of the American Society of Hematology, are just one piece of a larger effort by ASH to develop evidence-based guidelines on VTE management. More than 100 thrombosis experts have reviewed evidence and drafted more than 200 recommendations on diagnosis, prevention, and treatment of VTE, according to ASH.

The cancer-specific recommendations described by Dr. Lyman are based in part on a meta-analysis of 17 randomized controlled trials of cancer patients receiving LMWH thromboprophylaxis that were published between 2008 and 2017. Across cancer types and settings, LMWH prophylaxis in these trials was associated with a reduced risk of VTE and an increased risk of bleeding, Dr. Lyman said.

For all cancer types, relative risk (RR) of VTE was 0.55 (95% confidence interval, 0.46-0.65), with an absolute risk reduction of just 2.7% “because of the low baseline risk of VTE in this setting,” Dr. Lyman said.

However, the baseline risk increased for certain cancer types, including lung cancer, which had a similar relative risk of 0.53 (95% CI, 0.41-0.69) but an absolute risk reduction of 4.3%, according to data Dr. Lyman presented. Likewise, pancreatic cancer was associated with a relative risk of 0.43 (95% CI, 0.25-0.73) but an absolute risk reduction of 10.1%.

Major bleeding across all trials was significantly increased (RR 1.40; 95% CI, 1.01-1.92), but the presented data show that, in absolute terms, the increase was just 0.7% overall and similarly, 0.7% and 0.9% for lung and pancreatic cancer, respectively.

However, VTE risk depends on more than the site of the cancer, Dr. Lyman noted. In their deliberations, the panel considered the validated Khorana Risk Score, which incorporates factors such as body mass index, platelet count, leukocyte count, and hemoglobin level.

Specific analysis of high-risk patients suggested a pronounced risk reduction associated with LMWH prophylaxis, according to Dr. Lyman, who noted that a patient-level analysis including nearly 8,000 patients from 13 randomized, controlled trials showed a relative risk of 0.58, with VTE events seen in 4.0% patients in the LMWH group versus 7.0% of controls.

The forthcoming ASH guidelines also will address other aspects of cancer-associated VTE, according to Dr. Lyman, including initial treatment, secondary prophylaxis, perioperative prophylaxis, and prophylaxis or treatment in patients with a central venous catheter.

“The risk of venous thromboembolism in patients with cancer is well recognized, and that risk is especially notable in patients receiving cancer treatment,” Dr. Lyman said.

Dr. Lyman reported having no relevant financial disclosures.

hematologynews@frontlinemedcom.com

ATLANTA – An expert panel convened by the American Society of Hematology will recommend against routine venous thromboembolism (VTE) prophylaxis with low-molecular-weight heparin, except in patients deemed high risk, the panel chair told attendees at the group’s annual meeting.

The recommendations will be posted for public comment in early 2018 and are expected to be finalized and published later in the year.

The panel found strong evidence to recommend against prophylaxis in cancer patients at low risk of VTE, said Gary H. Lyman, MD, of the Fred Hutchinson Cancer Research Center and the University of Washington, both in Seattle.

For cancer patients at high risk of VTE, the panel will make a conditional recommendation – based on weaker evidence – in favor of low-molecular-weight thromboprophylaxis (LMWH) “with a caveat that patients should have no major bleeding risk or other contraindication to anticoagulation,” Dr. Lyman said.

The panel also found weaker evidence to support a conditional recommendation against routine prophylaxis in patients at intermediate risk of VTE, based on results from a systematic review.

These recommendations, which were described during a special education session at the annual meeting of the American Society of Hematology, are just one piece of a larger effort by ASH to develop evidence-based guidelines on VTE management. More than 100 thrombosis experts have reviewed evidence and drafted more than 200 recommendations on diagnosis, prevention, and treatment of VTE, according to ASH.

The cancer-specific recommendations described by Dr. Lyman are based in part on a meta-analysis of 17 randomized controlled trials of cancer patients receiving LMWH thromboprophylaxis that were published between 2008 and 2017. Across cancer types and settings, LMWH prophylaxis in these trials was associated with a reduced risk of VTE and an increased risk of bleeding, Dr. Lyman said.

For all cancer types, relative risk (RR) of VTE was 0.55 (95% confidence interval, 0.46-0.65), with an absolute risk reduction of just 2.7% “because of the low baseline risk of VTE in this setting,” Dr. Lyman said.

However, the baseline risk increased for certain cancer types, including lung cancer, which had a similar relative risk of 0.53 (95% CI, 0.41-0.69) but an absolute risk reduction of 4.3%, according to data Dr. Lyman presented. Likewise, pancreatic cancer was associated with a relative risk of 0.43 (95% CI, 0.25-0.73) but an absolute risk reduction of 10.1%.

Major bleeding across all trials was significantly increased (RR 1.40; 95% CI, 1.01-1.92), but the presented data show that, in absolute terms, the increase was just 0.7% overall and similarly, 0.7% and 0.9% for lung and pancreatic cancer, respectively.

However, VTE risk depends on more than the site of the cancer, Dr. Lyman noted. In their deliberations, the panel considered the validated Khorana Risk Score, which incorporates factors such as body mass index, platelet count, leukocyte count, and hemoglobin level.

Specific analysis of high-risk patients suggested a pronounced risk reduction associated with LMWH prophylaxis, according to Dr. Lyman, who noted that a patient-level analysis including nearly 8,000 patients from 13 randomized, controlled trials showed a relative risk of 0.58, with VTE events seen in 4.0% patients in the LMWH group versus 7.0% of controls.

The forthcoming ASH guidelines also will address other aspects of cancer-associated VTE, according to Dr. Lyman, including initial treatment, secondary prophylaxis, perioperative prophylaxis, and prophylaxis or treatment in patients with a central venous catheter.

“The risk of venous thromboembolism in patients with cancer is well recognized, and that risk is especially notable in patients receiving cancer treatment,” Dr. Lyman said.

Dr. Lyman reported having no relevant financial disclosures.

hematologynews@frontlinemedcom.com

ATLANTA – An oral investigational drug with specific activity against a mutation frequently found in advanced systemic mastocytosis (ASM) produced clinical responses in the majority treated patients, according to preliminary data presented at the annual meeting of the American Society of Hematology.

Mitchel L. Zoler/Frontline Medical News

Avapritinib, previously known as BLU-285, was well tolerated in the phase 1 trial, and demonstrated encouraging preliminary activity that included a 56% rate of complete or partial response, according to lead study author Daniel J. DeAngelo, MD, PhD, director of clinical and translational research at Dana-Farber Cancer Institute, Boston.

Currently, midostaurin, a multikinase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of systemic mastocytosis. That approval, announced in April 2017, was based in part on a 17% rate of complete or partial response, Dr. DeAngelo noted at a press briefing.

The primary goal of the phase 1 trial was to evaluate the safety profile and establish a maximum-tolerated dose for once-daily oral avapritinib administration. Treatment-emergent side effects were primarily grade 1-2, according to Dr. DeAngelo. Most hematologic toxicities were mild to moderate, and the most common grade 3 nonhematologic toxicities were periorbital edema and fatigue.

This part of the phase 1 trial enrolled 18 patients with ASM, systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and mantle cell lymphoma (MCL). Efficacy of avapritinib was assessed on International Working Group criteria for response rate in myelodysplasia.

The overall response rate was 72% (13 of 18 patients saw complete response, partial response, or clinical improvement), and a 56% rate of complete and partial response (10 of 18 patients), Dr. DeAngelo said.

Avapritinib was active in all ASM subtypes evaluated, including in patients who had previously been treated with midostaurin or chemotherapy, according to the investigators.

The data on avapritinib suggests the drug “has a potent and clinically important activity in systemic mastocytosis,” he said. “It has been a wonderful success in terms of getting the majority of patients into complete and partial remissions, and so as this evolves, having better targeted agents, I think, can improve the outcome for these patients.”

More patients are being enrolled as the phase 1 study continues into the dose-expansion phase at 300 mg once daily, and 30 of 32 patients remain on treatment with median duration of 9 months, Dr. DeAngelo said.

A phase 2 study in advanced systemic mastocytosis is planned for 2018, as well as phase 1 and phase 2 studies that will include patients with indolent or smoldering disease, he added.

Avapritinib is manufactured by Blueprint Medicines, which also supported the study. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.

SOURCE: DeAngelo D et al. ASH 2017 Abstract 2.

ATLANTA – An oral investigational drug with specific activity against a mutation frequently found in advanced systemic mastocytosis (ASM) produced clinical responses in the majority treated patients, according to preliminary data presented at the annual meeting of the American Society of Hematology.

Mitchel L. Zoler/Frontline Medical News

Avapritinib, previously known as BLU-285, was well tolerated in the phase 1 trial, and demonstrated encouraging preliminary activity that included a 56% rate of complete or partial response, according to lead study author Daniel J. DeAngelo, MD, PhD, director of clinical and translational research at Dana-Farber Cancer Institute, Boston.

Currently, midostaurin, a multikinase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of systemic mastocytosis. That approval, announced in April 2017, was based in part on a 17% rate of complete or partial response, Dr. DeAngelo noted at a press briefing.

The primary goal of the phase 1 trial was to evaluate the safety profile and establish a maximum-tolerated dose for once-daily oral avapritinib administration. Treatment-emergent side effects were primarily grade 1-2, according to Dr. DeAngelo. Most hematologic toxicities were mild to moderate, and the most common grade 3 nonhematologic toxicities were periorbital edema and fatigue.

This part of the phase 1 trial enrolled 18 patients with ASM, systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and mantle cell lymphoma (MCL). Efficacy of avapritinib was assessed on International Working Group criteria for response rate in myelodysplasia.

The overall response rate was 72% (13 of 18 patients saw complete response, partial response, or clinical improvement), and a 56% rate of complete and partial response (10 of 18 patients), Dr. DeAngelo said.

Avapritinib was active in all ASM subtypes evaluated, including in patients who had previously been treated with midostaurin or chemotherapy, according to the investigators.

The data on avapritinib suggests the drug “has a potent and clinically important activity in systemic mastocytosis,” he said. “It has been a wonderful success in terms of getting the majority of patients into complete and partial remissions, and so as this evolves, having better targeted agents, I think, can improve the outcome for these patients.”

More patients are being enrolled as the phase 1 study continues into the dose-expansion phase at 300 mg once daily, and 30 of 32 patients remain on treatment with median duration of 9 months, Dr. DeAngelo said.

A phase 2 study in advanced systemic mastocytosis is planned for 2018, as well as phase 1 and phase 2 studies that will include patients with indolent or smoldering disease, he added.

Avapritinib is manufactured by Blueprint Medicines, which also supported the study. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.

SOURCE: DeAngelo D et al. ASH 2017 Abstract 2.

ATLANTA – An oral investigational drug with specific activity against a mutation frequently found in advanced systemic mastocytosis (ASM) produced clinical responses in the majority treated patients, according to preliminary data presented at the annual meeting of the American Society of Hematology.

Mitchel L. Zoler/Frontline Medical News

Avapritinib, previously known as BLU-285, was well tolerated in the phase 1 trial, and demonstrated encouraging preliminary activity that included a 56% rate of complete or partial response, according to lead study author Daniel J. DeAngelo, MD, PhD, director of clinical and translational research at Dana-Farber Cancer Institute, Boston.

Currently, midostaurin, a multikinase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of systemic mastocytosis. That approval, announced in April 2017, was based in part on a 17% rate of complete or partial response, Dr. DeAngelo noted at a press briefing.

The primary goal of the phase 1 trial was to evaluate the safety profile and establish a maximum-tolerated dose for once-daily oral avapritinib administration. Treatment-emergent side effects were primarily grade 1-2, according to Dr. DeAngelo. Most hematologic toxicities were mild to moderate, and the most common grade 3 nonhematologic toxicities were periorbital edema and fatigue.

This part of the phase 1 trial enrolled 18 patients with ASM, systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and mantle cell lymphoma (MCL). Efficacy of avapritinib was assessed on International Working Group criteria for response rate in myelodysplasia.

The overall response rate was 72% (13 of 18 patients saw complete response, partial response, or clinical improvement), and a 56% rate of complete and partial response (10 of 18 patients), Dr. DeAngelo said.

Avapritinib was active in all ASM subtypes evaluated, including in patients who had previously been treated with midostaurin or chemotherapy, according to the investigators.

The data on avapritinib suggests the drug “has a potent and clinically important activity in systemic mastocytosis,” he said. “It has been a wonderful success in terms of getting the majority of patients into complete and partial remissions, and so as this evolves, having better targeted agents, I think, can improve the outcome for these patients.”

More patients are being enrolled as the phase 1 study continues into the dose-expansion phase at 300 mg once daily, and 30 of 32 patients remain on treatment with median duration of 9 months, Dr. DeAngelo said.

A phase 2 study in advanced systemic mastocytosis is planned for 2018, as well as phase 1 and phase 2 studies that will include patients with indolent or smoldering disease, he added.

Avapritinib is manufactured by Blueprint Medicines, which also supported the study. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.

SOURCE: DeAngelo D et al. ASH 2017 Abstract 2.

ATLANTA – Intrabone gene therapy could offer long-term hope for patients with beta thalassemia who cannot be treated by allogeneic hematopoietic stem cell transplant (HSCT), suggest the results of a phase 1/2 trial.

After a median of 16 months of follow-up, five of seven patients who received this novel gene therapy needed markedly fewer blood transfusions than at baseline, lead investigator Sarah Marktel, MD, reported at the annual meeting of the American Society of Hematology.

Amy Karon/Frontline Medical News

Even more strikingly, intrabone gene therapy obviated the need for blood transfusions in three children with beta-thalassemia, including one who is beta-0/beta-0 (indicating severe disease), said Dr. Marktel of San Raffaele Scientific Institute and San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milan.

All patients met the trial’s primary safety endpoint and experienced no treatment-related adverse effects except those caused by conditioning chemotherapy, such as infections, Dr. Marktel said. She and her coinvestigators are expanding the study by administering intrabone gene therapy to three more children.

Beta-thalassemia is a genetic anemia linked to multiple mutations of the beta-globin gene. Patients who can’t undergo allogeneic HSCT face a lifetime of blood transfusions and iron chelation. This is the reality for most because they lack a compatible donor, have exclusionary risk factors for allogeneic transplant, or cannot access treatment, Dr. Marktel said during a press briefing.

Although this is not the first human study of gene therapy in beta-thalassemia, it is the first to infuse treatment directly into bone marrow instead of peripheral blood.

“Compared to previous trials, patients showed evidence of successful engraftment [proliferation in bone marrow] sooner after receiving the therapy,” Dr. Marktel said. Researchers saw evidence of engraftment as soon as 10 days after treatment – noticeably faster than in prior gene therapy studies of beta-thalassemia, she added.

To develop this treatment, investigators created a self-inactivating lentiviral vector (dubbed GLOBE) that carries a normal beta-globin gene. The vector posted encouraging safety and efficacy signals in studies of human thalassemic cells and in a mouse model, Dr. Marktel said.

For the phase 1/2 trial, the researchers extracted circulating CD34+ stem cells from the peripheral blood from three adults and four children with transfusion-dependent beta-thalassemia. For each patient, they transduced these stem cells with GLOBE. Next, patients underwent a 3-day conditioning regimen of treosulfan and thiotepa, after which their individual cell-gene product was infused into their own bone marrow.

This is a small study, but if results hold up in more patients, gene therapy “could represent an alternative to bone marrow transplantation that does not require a matched donor or immunosuppression and that carries no risk of graft-versus-host disease or transplant rejection,” Dr. Marktel said. Children in this study might have had better results because their younger stem cells are more amenable to gene transduction and engraftment, she hypothesized.

Both beta-0/beta-0 patients in the study are children. One continues to need blood transfusions because he experiences a drop in genetically modified cells and vector copy numbers soon after each infusion of gene therapy. The other was treated more than a year ago and remains transfusion free.

“The beta-0/beta-0 genotype is toughest to treat with gene therapy,” Dr. Marktel noted. “In comparison, beta-0/beta+ or beta+/beta+ patients have the highest chances of becoming transfusion independent because they can contribute their own hemoglobin to the total hemoglobin output.”

Telethon Foundation provided funding. Dr. Marktel disclosed research funding from GlaxoSmithKline, which has licensed the therapy.

SOURCE: Marktel S et al. ASH 2017 Abstract 355.

ATLANTA – Intrabone gene therapy could offer long-term hope for patients with beta thalassemia who cannot be treated by allogeneic hematopoietic stem cell transplant (HSCT), suggest the results of a phase 1/2 trial.

After a median of 16 months of follow-up, five of seven patients who received this novel gene therapy needed markedly fewer blood transfusions than at baseline, lead investigator Sarah Marktel, MD, reported at the annual meeting of the American Society of Hematology.

Amy Karon/Frontline Medical News

Even more strikingly, intrabone gene therapy obviated the need for blood transfusions in three children with beta-thalassemia, including one who is beta-0/beta-0 (indicating severe disease), said Dr. Marktel of San Raffaele Scientific Institute and San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milan.

All patients met the trial’s primary safety endpoint and experienced no treatment-related adverse effects except those caused by conditioning chemotherapy, such as infections, Dr. Marktel said. She and her coinvestigators are expanding the study by administering intrabone gene therapy to three more children.

Beta-thalassemia is a genetic anemia linked to multiple mutations of the beta-globin gene. Patients who can’t undergo allogeneic HSCT face a lifetime of blood transfusions and iron chelation. This is the reality for most because they lack a compatible donor, have exclusionary risk factors for allogeneic transplant, or cannot access treatment, Dr. Marktel said during a press briefing.

Although this is not the first human study of gene therapy in beta-thalassemia, it is the first to infuse treatment directly into bone marrow instead of peripheral blood.

“Compared to previous trials, patients showed evidence of successful engraftment [proliferation in bone marrow] sooner after receiving the therapy,” Dr. Marktel said. Researchers saw evidence of engraftment as soon as 10 days after treatment – noticeably faster than in prior gene therapy studies of beta-thalassemia, she added.

To develop this treatment, investigators created a self-inactivating lentiviral vector (dubbed GLOBE) that carries a normal beta-globin gene. The vector posted encouraging safety and efficacy signals in studies of human thalassemic cells and in a mouse model, Dr. Marktel said.

For the phase 1/2 trial, the researchers extracted circulating CD34+ stem cells from the peripheral blood from three adults and four children with transfusion-dependent beta-thalassemia. For each patient, they transduced these stem cells with GLOBE. Next, patients underwent a 3-day conditioning regimen of treosulfan and thiotepa, after which their individual cell-gene product was infused into their own bone marrow.

This is a small study, but if results hold up in more patients, gene therapy “could represent an alternative to bone marrow transplantation that does not require a matched donor or immunosuppression and that carries no risk of graft-versus-host disease or transplant rejection,” Dr. Marktel said. Children in this study might have had better results because their younger stem cells are more amenable to gene transduction and engraftment, she hypothesized.

Both beta-0/beta-0 patients in the study are children. One continues to need blood transfusions because he experiences a drop in genetically modified cells and vector copy numbers soon after each infusion of gene therapy. The other was treated more than a year ago and remains transfusion free.

“The beta-0/beta-0 genotype is toughest to treat with gene therapy,” Dr. Marktel noted. “In comparison, beta-0/beta+ or beta+/beta+ patients have the highest chances of becoming transfusion independent because they can contribute their own hemoglobin to the total hemoglobin output.”

Telethon Foundation provided funding. Dr. Marktel disclosed research funding from GlaxoSmithKline, which has licensed the therapy.

SOURCE: Marktel S et al. ASH 2017 Abstract 355.

ATLANTA – Intrabone gene therapy could offer long-term hope for patients with beta thalassemia who cannot be treated by allogeneic hematopoietic stem cell transplant (HSCT), suggest the results of a phase 1/2 trial.

After a median of 16 months of follow-up, five of seven patients who received this novel gene therapy needed markedly fewer blood transfusions than at baseline, lead investigator Sarah Marktel, MD, reported at the annual meeting of the American Society of Hematology.

Amy Karon/Frontline Medical News

Even more strikingly, intrabone gene therapy obviated the need for blood transfusions in three children with beta-thalassemia, including one who is beta-0/beta-0 (indicating severe disease), said Dr. Marktel of San Raffaele Scientific Institute and San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milan.

All patients met the trial’s primary safety endpoint and experienced no treatment-related adverse effects except those caused by conditioning chemotherapy, such as infections, Dr. Marktel said. She and her coinvestigators are expanding the study by administering intrabone gene therapy to three more children.

Beta-thalassemia is a genetic anemia linked to multiple mutations of the beta-globin gene. Patients who can’t undergo allogeneic HSCT face a lifetime of blood transfusions and iron chelation. This is the reality for most because they lack a compatible donor, have exclusionary risk factors for allogeneic transplant, or cannot access treatment, Dr. Marktel said during a press briefing.

Although this is not the first human study of gene therapy in beta-thalassemia, it is the first to infuse treatment directly into bone marrow instead of peripheral blood.

“Compared to previous trials, patients showed evidence of successful engraftment [proliferation in bone marrow] sooner after receiving the therapy,” Dr. Marktel said. Researchers saw evidence of engraftment as soon as 10 days after treatment – noticeably faster than in prior gene therapy studies of beta-thalassemia, she added.

To develop this treatment, investigators created a self-inactivating lentiviral vector (dubbed GLOBE) that carries a normal beta-globin gene. The vector posted encouraging safety and efficacy signals in studies of human thalassemic cells and in a mouse model, Dr. Marktel said.

For the phase 1/2 trial, the researchers extracted circulating CD34+ stem cells from the peripheral blood from three adults and four children with transfusion-dependent beta-thalassemia. For each patient, they transduced these stem cells with GLOBE. Next, patients underwent a 3-day conditioning regimen of treosulfan and thiotepa, after which their individual cell-gene product was infused into their own bone marrow.

This is a small study, but if results hold up in more patients, gene therapy “could represent an alternative to bone marrow transplantation that does not require a matched donor or immunosuppression and that carries no risk of graft-versus-host disease or transplant rejection,” Dr. Marktel said. Children in this study might have had better results because their younger stem cells are more amenable to gene transduction and engraftment, she hypothesized.

Both beta-0/beta-0 patients in the study are children. One continues to need blood transfusions because he experiences a drop in genetically modified cells and vector copy numbers soon after each infusion of gene therapy. The other was treated more than a year ago and remains transfusion free.

“The beta-0/beta-0 genotype is toughest to treat with gene therapy,” Dr. Marktel noted. “In comparison, beta-0/beta+ or beta+/beta+ patients have the highest chances of becoming transfusion independent because they can contribute their own hemoglobin to the total hemoglobin output.”

Telethon Foundation provided funding. Dr. Marktel disclosed research funding from GlaxoSmithKline, which has licensed the therapy.

SOURCE: Marktel S et al. ASH 2017 Abstract 355.

The Commission on Cancer (CoC) of the American College of Surgeons (ACS) has granted its mid-year 2017 Outstanding Achievement Award to a select group of 16 accredited cancer programs throughout the U.S. Award criteria are based on qualitative and quantitative surveys conducted in the first half of 2017. Visit the ACS website for a list of these award-winning cancer programs at facs.org/quality-programs/cancer/coc/info/outstanding/2017-part-1.

The purpose of the award is to raise the bar on quality cancer care, with the ultimate goal of increasing awareness about quality care choices among cancer patients and their loved ones. In addition, the award is intended to fulfill the following goals:

• Recognize those cancer programs that achieve excellence in providing quality care to cancer patients

• Motivate other cancer programs to work toward improving their level of care

• Facilitate dialogue between award recipients and health care professionals at other cancer facilities for the purpose of sharing best practices

• Encourage honorees to serve as quality care resources to other cancer programs



“More and more, we’re finding that patients and their families want to know how the health care institutions in their communities compare with one another,” said Lawrence N. Shulman, MD, FACP, Chair of the CoC. “They want access to information in terms of who’s providing the best quality of care, and they want to know about overall patient outcomes. Through this recognition program, I’d like to think we’re playing a small, but vital, role in helping them make informed decisions on their cancer care. ”The 16 award-winning cancer care programs represent approximately six percent of programs surveyed by the CoC January 1–June 30, 2017. “These cancer programs currently represent the best of the best when it comes to cancer care,” Dr. Shulman added.
 

The Commission on Cancer (CoC) of the American College of Surgeons (ACS) has granted its mid-year 2017 Outstanding Achievement Award to a select group of 16 accredited cancer programs throughout the U.S. Award criteria are based on qualitative and quantitative surveys conducted in the first half of 2017. Visit the ACS website for a list of these award-winning cancer programs at facs.org/quality-programs/cancer/coc/info/outstanding/2017-part-1.

The purpose of the award is to raise the bar on quality cancer care, with the ultimate goal of increasing awareness about quality care choices among cancer patients and their loved ones. In addition, the award is intended to fulfill the following goals:

• Recognize those cancer programs that achieve excellence in providing quality care to cancer patients

• Motivate other cancer programs to work toward improving their level of care

• Facilitate dialogue between award recipients and health care professionals at other cancer facilities for the purpose of sharing best practices

• Encourage honorees to serve as quality care resources to other cancer programs



“More and more, we’re finding that patients and their families want to know how the health care institutions in their communities compare with one another,” said Lawrence N. Shulman, MD, FACP, Chair of the CoC. “They want access to information in terms of who’s providing the best quality of care, and they want to know about overall patient outcomes. Through this recognition program, I’d like to think we’re playing a small, but vital, role in helping them make informed decisions on their cancer care. ”The 16 award-winning cancer care programs represent approximately six percent of programs surveyed by the CoC January 1–June 30, 2017. “These cancer programs currently represent the best of the best when it comes to cancer care,” Dr. Shulman added.
 

The Commission on Cancer (CoC) of the American College of Surgeons (ACS) has granted its mid-year 2017 Outstanding Achievement Award to a select group of 16 accredited cancer programs throughout the U.S. Award criteria are based on qualitative and quantitative surveys conducted in the first half of 2017. Visit the ACS website for a list of these award-winning cancer programs at facs.org/quality-programs/cancer/coc/info/outstanding/2017-part-1.

The purpose of the award is to raise the bar on quality cancer care, with the ultimate goal of increasing awareness about quality care choices among cancer patients and their loved ones. In addition, the award is intended to fulfill the following goals:

• Recognize those cancer programs that achieve excellence in providing quality care to cancer patients

• Motivate other cancer programs to work toward improving their level of care

• Facilitate dialogue between award recipients and health care professionals at other cancer facilities for the purpose of sharing best practices

• Encourage honorees to serve as quality care resources to other cancer programs



“More and more, we’re finding that patients and their families want to know how the health care institutions in their communities compare with one another,” said Lawrence N. Shulman, MD, FACP, Chair of the CoC. “They want access to information in terms of who’s providing the best quality of care, and they want to know about overall patient outcomes. Through this recognition program, I’d like to think we’re playing a small, but vital, role in helping them make informed decisions on their cancer care. ”The 16 award-winning cancer care programs represent approximately six percent of programs surveyed by the CoC January 1–June 30, 2017. “These cancer programs currently represent the best of the best when it comes to cancer care,” Dr. Shulman added.
 

Frank G. Opelka, MD, FACS, Medical Director, Quality and Health Policy, American College of Surgeons (ACS) Division of Advocacy and Health Policy, testified November 8 before the U.S. House Committee on Energy and Commerce Health Subcommittee. The subcommittee conducted the hearing—MACRA (Medicare Access and CHIP [Children’s Health Insurance Program] Reauthorization Act) and Alternative Payment Models: Developing Options for Value-based Care—to explore how Medicare payment reforms are shaping the way physicians treat patients.

Dr. Opelka described for lawmakers how the Advanced Alternative Payment Model (A-APM) developed by the ACS and Brandeis University, Waltham, MA, the ACS-Brandeis A-APM—proceeded through the Payment Model Technical Advisory Committee (PTAC) review and approval process. He shared how the ACS-Brandeis A-APM can revolutionize physician payment, as well as encourage and incentivize a team-based approach to patient care. Dr. Opelka expressed the College’s ongoing willingness to work with Congress on ways to improve and enhance patient care and Medicare physician payment.

A replay of the hearing is available on the Energy and Commerce Committee website at https://goo.gl/X2xjqJ.

For more information, contact Matt Coffron, ACS Manager of Policy Development, at mcoffron@facs.org.
 

Frank G. Opelka, MD, FACS, Medical Director, Quality and Health Policy, American College of Surgeons (ACS) Division of Advocacy and Health Policy, testified November 8 before the U.S. House Committee on Energy and Commerce Health Subcommittee. The subcommittee conducted the hearing—MACRA (Medicare Access and CHIP [Children’s Health Insurance Program] Reauthorization Act) and Alternative Payment Models: Developing Options for Value-based Care—to explore how Medicare payment reforms are shaping the way physicians treat patients.

Dr. Opelka described for lawmakers how the Advanced Alternative Payment Model (A-APM) developed by the ACS and Brandeis University, Waltham, MA, the ACS-Brandeis A-APM—proceeded through the Payment Model Technical Advisory Committee (PTAC) review and approval process. He shared how the ACS-Brandeis A-APM can revolutionize physician payment, as well as encourage and incentivize a team-based approach to patient care. Dr. Opelka expressed the College’s ongoing willingness to work with Congress on ways to improve and enhance patient care and Medicare physician payment.

A replay of the hearing is available on the Energy and Commerce Committee website at https://goo.gl/X2xjqJ.

For more information, contact Matt Coffron, ACS Manager of Policy Development, at mcoffron@facs.org.
 

Frank G. Opelka, MD, FACS, Medical Director, Quality and Health Policy, American College of Surgeons (ACS) Division of Advocacy and Health Policy, testified November 8 before the U.S. House Committee on Energy and Commerce Health Subcommittee. The subcommittee conducted the hearing—MACRA (Medicare Access and CHIP [Children’s Health Insurance Program] Reauthorization Act) and Alternative Payment Models: Developing Options for Value-based Care—to explore how Medicare payment reforms are shaping the way physicians treat patients.

Dr. Opelka described for lawmakers how the Advanced Alternative Payment Model (A-APM) developed by the ACS and Brandeis University, Waltham, MA, the ACS-Brandeis A-APM—proceeded through the Payment Model Technical Advisory Committee (PTAC) review and approval process. He shared how the ACS-Brandeis A-APM can revolutionize physician payment, as well as encourage and incentivize a team-based approach to patient care. Dr. Opelka expressed the College’s ongoing willingness to work with Congress on ways to improve and enhance patient care and Medicare physician payment.

A replay of the hearing is available on the Energy and Commerce Committee website at https://goo.gl/X2xjqJ.

For more information, contact Matt Coffron, ACS Manager of Policy Development, at mcoffron@facs.org.
 

The American College of Surgeons (ACS) 2018 Nominating Committee of the Fellows (NCF) and the Nominating Committee of the Board of Governors (NCBG) will be selecting nominees for leadership positions in the College as follows.

Call for nominations for Officers-Elect

The 2018 NCF will select nominees for the three Officer-Elect positions of the ACS: President-Elect, First Vice-President-Elect, and Second Vice-President-Elect. The deadline for submitting nominations is February 23, 2018.

Criteria for consideration

The NCF will use the following guidelines when considering potential candidates:

• Nominees must be loyal members of the College who have demonstrated outstanding integrity and an unquestioned devotion to the highest principles of surgical practice.

• Nominees must have demonstrated leadership qualities, such as service and active participation on ACS committees or in other components of the College.

• The ACS encourages consideration of women and underrepresented minorities for all leadership positions.

All nominations must include the following:

• A letter/letters of nomination

• A personal statement from the candidate detailing his or her ACS service and interest in the position (for President-Elect position only)

• A current curriculum vitae (CV)

• The name of one individual who can serve as a reference



Further details

Entities such as surgical specialty societies, ACS Advisory Councils, ACS committees, and ACS chapters that would like to provide a letter of nomination must provide a description of their selection process and the total list of applicants reviewed.

Any attempt to contact members of the NCF by a candidate or on behalf of a candidate will be viewed negatively, and may result in disqualification. Applications submitted without the requested information will not be considered.

Nominations must be submitted to officerandbrnominations@facs.org. If you have any questions, contact Emily Kalata at 312-202-5360 or ekalata@facs.org.

Call for Nominations for Board of Regents

The 2018 NCBG will select nominees for pending vacancies on the Board of Regents to be filled at Clinical Congress 2018. The deadline for submitting nominations is February 23, 2018.

Criteria

The NCBG will use the following guidelines when considering potential candidates:

• Nominees must be loyal members of the College who have demonstrated outstanding integrity along with an unquestioned devotion to the highest principles of surgical practice.

• Nominees must have demonstrated leadership qualities, such as service and active participation on ACS committees or in other components of the College.

• The ACS encourages consideration of women and underrepresented minorities for all leadership positions.

• The NCBG recognizes the importance of the Board of Regents representing all who practice surgery in both academic and community practice, regardless of practice location or configuration.

• Nominations are open to surgeons of all specialties, but particular consideration will be given this nomination cycle to those in the following specialties:

o Burn and critical care surgery

o Gastrointestinal surgery

o General surgery

o Surgical oncology

o Transplantation

o Trauma

o Vascular surgery

Only individuals who are currently and expected to remain in active surgical practice for their entire term may be nominated for election or reelection to the Board of Regents.

All nominations must include the following:

• A letter of nomination

• A personal statement from the candidate detailing his or her ACS service and interest in the position

• A current curriculum vitae

• The name of one individual who can serve as a reference



Further details

Entities such as surgical specialty societies, ACS Advisory Councils, ACS Committees, and ACS chapters that would like to provide a letter of nomination must provide at least two nominees and a description of their selection process along with the total list of applicants reviewed.

Any attempt to contact members of the NCBG by a candidate or on behalf of a candidate will be viewed negatively, and may possibly result in disqualification. Applications submitted without the requested information will not be considered.

Nominations may be submitted to officerandbrnominations@facs.org. If you have any questions, contact Emily Kalata at 312-202-5360 or ekalata@facs.org.

For information only, the current members of the Board of Regents who will be considered for re-election are (all MD, FACS): John L. D. Atkinson, James C. Denneny III, Timothy J. Eberlein, Henri R. Ford, Enrique Hernandez, L. Scott Levin, Linda Phillips, Anton A. Sidawy, Beth H. Sutton, and Steven D. Wexner.

The American College of Surgeons (ACS) 2018 Nominating Committee of the Fellows (NCF) and the Nominating Committee of the Board of Governors (NCBG) will be selecting nominees for leadership positions in the College as follows.

Call for nominations for Officers-Elect

The 2018 NCF will select nominees for the three Officer-Elect positions of the ACS: President-Elect, First Vice-President-Elect, and Second Vice-President-Elect. The deadline for submitting nominations is February 23, 2018.

Criteria for consideration

The NCF will use the following guidelines when considering potential candidates:

• Nominees must be loyal members of the College who have demonstrated outstanding integrity and an unquestioned devotion to the highest principles of surgical practice.

• Nominees must have demonstrated leadership qualities, such as service and active participation on ACS committees or in other components of the College.

• The ACS encourages consideration of women and underrepresented minorities for all leadership positions.

All nominations must include the following:

• A letter/letters of nomination

• A personal statement from the candidate detailing his or her ACS service and interest in the position (for President-Elect position only)

• A current curriculum vitae (CV)

• The name of one individual who can serve as a reference



Further details

Entities such as surgical specialty societies, ACS Advisory Councils, ACS committees, and ACS chapters that would like to provide a letter of nomination must provide a description of their selection process and the total list of applicants reviewed.

Any attempt to contact members of the NCF by a candidate or on behalf of a candidate will be viewed negatively, and may result in disqualification. Applications submitted without the requested information will not be considered.

Nominations must be submitted to officerandbrnominations@facs.org. If you have any questions, contact Emily Kalata at 312-202-5360 or ekalata@facs.org.

Call for Nominations for Board of Regents

The 2018 NCBG will select nominees for pending vacancies on the Board of Regents to be filled at Clinical Congress 2018. The deadline for submitting nominations is February 23, 2018.

Criteria

The NCBG will use the following guidelines when considering potential candidates:

• Nominees must be loyal members of the College who have demonstrated outstanding integrity along with an unquestioned devotion to the highest principles of surgical practice.

• Nominees must have demonstrated leadership qualities, such as service and active participation on ACS committees or in other components of the College.

• The ACS encourages consideration of women and underrepresented minorities for all leadership positions.

• The NCBG recognizes the importance of the Board of Regents representing all who practice surgery in both academic and community practice, regardless of practice location or configuration.

• Nominations are open to surgeons of all specialties, but particular consideration will be given this nomination cycle to those in the following specialties:

o Burn and critical care surgery

o Gastrointestinal surgery

o General surgery

o Surgical oncology

o Transplantation

o Trauma

o Vascular surgery

Only individuals who are currently and expected to remain in active surgical practice for their entire term may be nominated for election or reelection to the Board of Regents.

All nominations must include the following:

• A letter of nomination

• A personal statement from the candidate detailing his or her ACS service and interest in the position

• A current curriculum vitae

• The name of one individual who can serve as a reference



Further details

Entities such as surgical specialty societies, ACS Advisory Councils, ACS Committees, and ACS chapters that would like to provide a letter of nomination must provide at least two nominees and a description of their selection process along with the total list of applicants reviewed.

Any attempt to contact members of the NCBG by a candidate or on behalf of a candidate will be viewed negatively, and may possibly result in disqualification. Applications submitted without the requested information will not be considered.

Nominations may be submitted to officerandbrnominations@facs.org. If you have any questions, contact Emily Kalata at 312-202-5360 or ekalata@facs.org.

For information only, the current members of the Board of Regents who will be considered for re-election are (all MD, FACS): John L. D. Atkinson, James C. Denneny III, Timothy J. Eberlein, Henri R. Ford, Enrique Hernandez, L. Scott Levin, Linda Phillips, Anton A. Sidawy, Beth H. Sutton, and Steven D. Wexner.

The American College of Surgeons (ACS) 2018 Nominating Committee of the Fellows (NCF) and the Nominating Committee of the Board of Governors (NCBG) will be selecting nominees for leadership positions in the College as follows.

Call for nominations for Officers-Elect

The 2018 NCF will select nominees for the three Officer-Elect positions of the ACS: President-Elect, First Vice-President-Elect, and Second Vice-President-Elect. The deadline for submitting nominations is February 23, 2018.

Criteria for consideration

The NCF will use the following guidelines when considering potential candidates:

• Nominees must be loyal members of the College who have demonstrated outstanding integrity and an unquestioned devotion to the highest principles of surgical practice.

• Nominees must have demonstrated leadership qualities, such as service and active participation on ACS committees or in other components of the College.

• The ACS encourages consideration of women and underrepresented minorities for all leadership positions.

All nominations must include the following:

• A letter/letters of nomination

• A personal statement from the candidate detailing his or her ACS service and interest in the position (for President-Elect position only)

• A current curriculum vitae (CV)

• The name of one individual who can serve as a reference



Further details

Entities such as surgical specialty societies, ACS Advisory Councils, ACS committees, and ACS chapters that would like to provide a letter of nomination must provide a description of their selection process and the total list of applicants reviewed.

Any attempt to contact members of the NCF by a candidate or on behalf of a candidate will be viewed negatively, and may result in disqualification. Applications submitted without the requested information will not be considered.

Nominations must be submitted to officerandbrnominations@facs.org. If you have any questions, contact Emily Kalata at 312-202-5360 or ekalata@facs.org.

Call for Nominations for Board of Regents

The 2018 NCBG will select nominees for pending vacancies on the Board of Regents to be filled at Clinical Congress 2018. The deadline for submitting nominations is February 23, 2018.

Criteria

The NCBG will use the following guidelines when considering potential candidates:

• Nominees must be loyal members of the College who have demonstrated outstanding integrity along with an unquestioned devotion to the highest principles of surgical practice.

• Nominees must have demonstrated leadership qualities, such as service and active participation on ACS committees or in other components of the College.

• The ACS encourages consideration of women and underrepresented minorities for all leadership positions.

• The NCBG recognizes the importance of the Board of Regents representing all who practice surgery in both academic and community practice, regardless of practice location or configuration.

• Nominations are open to surgeons of all specialties, but particular consideration will be given this nomination cycle to those in the following specialties:

o Burn and critical care surgery

o Gastrointestinal surgery

o General surgery

o Surgical oncology

o Transplantation

o Trauma

o Vascular surgery

Only individuals who are currently and expected to remain in active surgical practice for their entire term may be nominated for election or reelection to the Board of Regents.

All nominations must include the following:

• A letter of nomination

• A personal statement from the candidate detailing his or her ACS service and interest in the position

• A current curriculum vitae

• The name of one individual who can serve as a reference



Further details

Entities such as surgical specialty societies, ACS Advisory Councils, ACS Committees, and ACS chapters that would like to provide a letter of nomination must provide at least two nominees and a description of their selection process along with the total list of applicants reviewed.

Any attempt to contact members of the NCBG by a candidate or on behalf of a candidate will be viewed negatively, and may possibly result in disqualification. Applications submitted without the requested information will not be considered.

Nominations may be submitted to officerandbrnominations@facs.org. If you have any questions, contact Emily Kalata at 312-202-5360 or ekalata@facs.org.

For information only, the current members of the Board of Regents who will be considered for re-election are (all MD, FACS): John L. D. Atkinson, James C. Denneny III, Timothy J. Eberlein, Henri R. Ford, Enrique Hernandez, L. Scott Levin, Linda Phillips, Anton A. Sidawy, Beth H. Sutton, and Steven D. Wexner.

Ronald V. Maier, MD, FACS, the Jane and Donald D. Trunkey Endowed Chair in Trauma Surgery, vice-chairman, department of surgery, and professor of surgery, University of Washington School of Medicine, Seattle, was elected President-Elect of the American College of Surgeons (ACS) at the October 25 Annual Business Meeting of the Members.

Ronald V. Maier, MD, FACS, the Jane and Donald D. Trunkey Endowed Chair in Trauma Surgery, vice-chairman, department of surgery, and professor of surgery, University of Washington School of Medicine, Seattle, was elected President-Elect of the American College of Surgeons (ACS) at the October 25 Annual Business Meeting of the Members.

Ronald V. Maier, MD, FACS, the Jane and Donald D. Trunkey Endowed Chair in Trauma Surgery, vice-chairman, department of surgery, and professor of surgery, University of Washington School of Medicine, Seattle, was elected President-Elect of the American College of Surgeons (ACS) at the October 25 Annual Business Meeting of the Members.

The December issue of the Bulletin of the American College of Surgeons is now available online at bulletin.facs.org. This month’s Bulletin includes the following features, columns, and news stories, among other:

Features

-Presidential Address: The joy and privilege of a surgical career

-ACS leaders visit Cuba, discover opportunities for collaboration

-Blockchain technology in health care: A primer for surgeons
 

Columns

-Looking forward: Highlights of College activities in 2017

-What surgeons should know about…The 2018 Inpatient Prospective Payment System final rule

-From residency to retirement: ACS Health Policy Scholar reports on the value of small acts
 

News

-ACSPA-SurgeonsPAC 2017–2018 election cycle update

-Medicare participation: Know your options

-Making quality stick: Optimal Resources for Surgical Quality and Safety: The SQSC and credentialing and privileging processes ensure sustainability of standards



The Bulletin is available in a variety of digital formats to satisfy every reader’s preference, including an interactive version and a smartphone app. Go to the Bulletin website at bulletin.facs.org to connect to any of these versions or to read the articles directly online.

The December issue of the Bulletin of the American College of Surgeons is now available online at bulletin.facs.org. This month’s Bulletin includes the following features, columns, and news stories, among other:

Features

-Presidential Address: The joy and privilege of a surgical career

-ACS leaders visit Cuba, discover opportunities for collaboration

-Blockchain technology in health care: A primer for surgeons
 

Columns

-Looking forward: Highlights of College activities in 2017

-What surgeons should know about…The 2018 Inpatient Prospective Payment System final rule

-From residency to retirement: ACS Health Policy Scholar reports on the value of small acts
 

News

-ACSPA-SurgeonsPAC 2017–2018 election cycle update

-Medicare participation: Know your options

-Making quality stick: Optimal Resources for Surgical Quality and Safety: The SQSC and credentialing and privileging processes ensure sustainability of standards



The Bulletin is available in a variety of digital formats to satisfy every reader’s preference, including an interactive version and a smartphone app. Go to the Bulletin website at bulletin.facs.org to connect to any of these versions or to read the articles directly online.

The December issue of the Bulletin of the American College of Surgeons is now available online at bulletin.facs.org. This month’s Bulletin includes the following features, columns, and news stories, among other:

Features

-Presidential Address: The joy and privilege of a surgical career

-ACS leaders visit Cuba, discover opportunities for collaboration

-Blockchain technology in health care: A primer for surgeons
 

Columns

-Looking forward: Highlights of College activities in 2017

-What surgeons should know about…The 2018 Inpatient Prospective Payment System final rule

-From residency to retirement: ACS Health Policy Scholar reports on the value of small acts
 

News

-ACSPA-SurgeonsPAC 2017–2018 election cycle update

-Medicare participation: Know your options

-Making quality stick: Optimal Resources for Surgical Quality and Safety: The SQSC and credentialing and privileging processes ensure sustainability of standards



The Bulletin is available in a variety of digital formats to satisfy every reader’s preference, including an interactive version and a smartphone app. Go to the Bulletin website at bulletin.facs.org to connect to any of these versions or to read the articles directly online.

ATLANTA – A single infusion of valoctocogene roxaparvovec normalized or nearly normalized factor VIII levels in 11 of 13 adults with severe hemophilia A, eliminated spontaneous bleeds and the need for factor VIII infusions, showed durable effects for up to 72 weeks of follow-up, K. John Pasi, MD, said at the annual meeting of the American Society of Hematology.

Amy Karon/Frontline Medical News

This is the first report of a successful study of gene therapy for hemophilia A in humans. Nicknamed valrox and designated as a breakthrough therapy by the Food and Drug Administration in October 2017, valoctocogene roxaparvovec uses an adenoviral vector to deliver a functional copy of the factor VIII gene to patients with hemophilia A, said Dr. Pasi of Barts and The London School of Medicine and Dentistry.

Gene therapy has long been the “holy grail” for managing hemophilia because it is a single-gene disorder with a clear relationship between clotting factor level and bleeding severity, Dr. Pasi said. In a mouse model of hemophilia A, valrox restored factor VIII plasma concentrations to levels thought to be adequate to support normal clotting in humans.

Accordingly, the phase 2/3 enrolled 13 patients with severe hemophilia A whose baseline factor VIII levels were less than 1 IU/dL. Patients started at the lowest dose of gene therapy (4 x 10¹³ vector genomes/kg) and then received a higher dose ( 6 x 10¹³ VG/kg) if their factor VIII level remained under 5 IU/dL at week 3. Six patients received the lower dose and seven received the higher dose.

At 78 weeks, median factor VIII level in the higher-dose cohort was 90 IU/mL, as Dr. Pasi and his associates reported simultaneously in the New England Journal of Medicine (2017 Dec 9. doi: 10. 1056/NEJMoa1708483).

Before undergoing gene therapy, study participants had endured up to 41 breakthrough bleeds per year despite often receiving more than 150 infusions of factor VIII annually. Median annualized bleeding rates, which at baseline were 16.5 in the higher dose group and 8 in the lower dose group, zeroed out in both groups after factor VIII activity rose above 5%. Quality of life was evaluated in five patients, who reported substantial improvements across all domains.

All patients began producing factor VIII several weeks after infusion. Median levels plateaued within normal range by 20 weeks in the higher-dose group. At the lower dose, median levels rose steadily to a median of 34 IU/dL by 20 weeks. Additionally, three recipients of the lower dose who were followed for 32 weeks achieved factor VIII levels within normal range (median 51 IU/dL). Levels of factor VIII remained within normal range for up to 78 weeks of posttreatment follow-up, Dr. Pasi said.

No patients developed inhibitors or signs of immune-related adverse effects, nor were adverse events qualitatively different between dose groups, Dr. Pasi said. The most common adverse effects were transient increases in alanine transaminase (ALT), which peaked between 44 IU/L and 141 IU/L and lasted anywhere from several days to 15 weeks. Patients whose ALT rose 1.5-fold above baseline received short-term corticosteroids with no adverse effects. All but one was tapered off. There were two serious adverse events – one elective knee surgery and one case of transient fever, headache, and myalgia at time of infusion.

So far, valrox appears to be long lasting, but “durability is a huge question for any gene therapy approach,” Dr. Pasi said. “The only way to answer it is to follow patients through.”

In hemophilia B, studies indicate that some patients continue expressing factor IX years after a single infusion of gene therapy (N Engl J Med. 2017 Dec 7;377:2215-27).

Two phase 3 trials will further evaluate safety and optimal dosing of valrox, Dr. Pasi said. The GENEr8-1 trial will use the 6 x 10¹³ VG/kg dose and the GENEr8-2 trial will use the 4 x 10¹³ VG/kg dose. Like the pilot study, these trials will exclude patients with inhibitors, but they may include patients with comorbidities such as liver disease, he said.

Valrox was previously known as BMN 270.

The study was sponsored by BioMarin. Dr. Pasi disclosed research funding, consultancy fees, and speaker and advisory relationships with BioMarin. He disclosed ties to many other companies that develop hemophilia therapies.

SOURCE: Pasi KJ et al. ASH 2017 Abstract 603

ATLANTA – A single infusion of valoctocogene roxaparvovec normalized or nearly normalized factor VIII levels in 11 of 13 adults with severe hemophilia A, eliminated spontaneous bleeds and the need for factor VIII infusions, showed durable effects for up to 72 weeks of follow-up, K. John Pasi, MD, said at the annual meeting of the American Society of Hematology.

Amy Karon/Frontline Medical News

This is the first report of a successful study of gene therapy for hemophilia A in humans. Nicknamed valrox and designated as a breakthrough therapy by the Food and Drug Administration in October 2017, valoctocogene roxaparvovec uses an adenoviral vector to deliver a functional copy of the factor VIII gene to patients with hemophilia A, said Dr. Pasi of Barts and The London School of Medicine and Dentistry.

Gene therapy has long been the “holy grail” for managing hemophilia because it is a single-gene disorder with a clear relationship between clotting factor level and bleeding severity, Dr. Pasi said. In a mouse model of hemophilia A, valrox restored factor VIII plasma concentrations to levels thought to be adequate to support normal clotting in humans.

Accordingly, the phase 2/3 enrolled 13 patients with severe hemophilia A whose baseline factor VIII levels were less than 1 IU/dL. Patients started at the lowest dose of gene therapy (4 x 10¹³ vector genomes/kg) and then received a higher dose ( 6 x 10¹³ VG/kg) if their factor VIII level remained under 5 IU/dL at week 3. Six patients received the lower dose and seven received the higher dose.

At 78 weeks, median factor VIII level in the higher-dose cohort was 90 IU/mL, as Dr. Pasi and his associates reported simultaneously in the New England Journal of Medicine (2017 Dec 9. doi: 10. 1056/NEJMoa1708483).

Before undergoing gene therapy, study participants had endured up to 41 breakthrough bleeds per year despite often receiving more than 150 infusions of factor VIII annually. Median annualized bleeding rates, which at baseline were 16.5 in the higher dose group and 8 in the lower dose group, zeroed out in both groups after factor VIII activity rose above 5%. Quality of life was evaluated in five patients, who reported substantial improvements across all domains.

All patients began producing factor VIII several weeks after infusion. Median levels plateaued within normal range by 20 weeks in the higher-dose group. At the lower dose, median levels rose steadily to a median of 34 IU/dL by 20 weeks. Additionally, three recipients of the lower dose who were followed for 32 weeks achieved factor VIII levels within normal range (median 51 IU/dL). Levels of factor VIII remained within normal range for up to 78 weeks of posttreatment follow-up, Dr. Pasi said.

No patients developed inhibitors or signs of immune-related adverse effects, nor were adverse events qualitatively different between dose groups, Dr. Pasi said. The most common adverse effects were transient increases in alanine transaminase (ALT), which peaked between 44 IU/L and 141 IU/L and lasted anywhere from several days to 15 weeks. Patients whose ALT rose 1.5-fold above baseline received short-term corticosteroids with no adverse effects. All but one was tapered off. There were two serious adverse events – one elective knee surgery and one case of transient fever, headache, and myalgia at time of infusion.

So far, valrox appears to be long lasting, but “durability is a huge question for any gene therapy approach,” Dr. Pasi said. “The only way to answer it is to follow patients through.”

In hemophilia B, studies indicate that some patients continue expressing factor IX years after a single infusion of gene therapy (N Engl J Med. 2017 Dec 7;377:2215-27).

Two phase 3 trials will further evaluate safety and optimal dosing of valrox, Dr. Pasi said. The GENEr8-1 trial will use the 6 x 10¹³ VG/kg dose and the GENEr8-2 trial will use the 4 x 10¹³ VG/kg dose. Like the pilot study, these trials will exclude patients with inhibitors, but they may include patients with comorbidities such as liver disease, he said.

Valrox was previously known as BMN 270.

The study was sponsored by BioMarin. Dr. Pasi disclosed research funding, consultancy fees, and speaker and advisory relationships with BioMarin. He disclosed ties to many other companies that develop hemophilia therapies.

SOURCE: Pasi KJ et al. ASH 2017 Abstract 603

ATLANTA – A single infusion of valoctocogene roxaparvovec normalized or nearly normalized factor VIII levels in 11 of 13 adults with severe hemophilia A, eliminated spontaneous bleeds and the need for factor VIII infusions, showed durable effects for up to 72 weeks of follow-up, K. John Pasi, MD, said at the annual meeting of the American Society of Hematology.

Amy Karon/Frontline Medical News

This is the first report of a successful study of gene therapy for hemophilia A in humans. Nicknamed valrox and designated as a breakthrough therapy by the Food and Drug Administration in October 2017, valoctocogene roxaparvovec uses an adenoviral vector to deliver a functional copy of the factor VIII gene to patients with hemophilia A, said Dr. Pasi of Barts and The London School of Medicine and Dentistry.

Gene therapy has long been the “holy grail” for managing hemophilia because it is a single-gene disorder with a clear relationship between clotting factor level and bleeding severity, Dr. Pasi said. In a mouse model of hemophilia A, valrox restored factor VIII plasma concentrations to levels thought to be adequate to support normal clotting in humans.

Accordingly, the phase 2/3 enrolled 13 patients with severe hemophilia A whose baseline factor VIII levels were less than 1 IU/dL. Patients started at the lowest dose of gene therapy (4 x 10¹³ vector genomes/kg) and then received a higher dose ( 6 x 10¹³ VG/kg) if their factor VIII level remained under 5 IU/dL at week 3. Six patients received the lower dose and seven received the higher dose.

At 78 weeks, median factor VIII level in the higher-dose cohort was 90 IU/mL, as Dr. Pasi and his associates reported simultaneously in the New England Journal of Medicine (2017 Dec 9. doi: 10. 1056/NEJMoa1708483).

Before undergoing gene therapy, study participants had endured up to 41 breakthrough bleeds per year despite often receiving more than 150 infusions of factor VIII annually. Median annualized bleeding rates, which at baseline were 16.5 in the higher dose group and 8 in the lower dose group, zeroed out in both groups after factor VIII activity rose above 5%. Quality of life was evaluated in five patients, who reported substantial improvements across all domains.

All patients began producing factor VIII several weeks after infusion. Median levels plateaued within normal range by 20 weeks in the higher-dose group. At the lower dose, median levels rose steadily to a median of 34 IU/dL by 20 weeks. Additionally, three recipients of the lower dose who were followed for 32 weeks achieved factor VIII levels within normal range (median 51 IU/dL). Levels of factor VIII remained within normal range for up to 78 weeks of posttreatment follow-up, Dr. Pasi said.

No patients developed inhibitors or signs of immune-related adverse effects, nor were adverse events qualitatively different between dose groups, Dr. Pasi said. The most common adverse effects were transient increases in alanine transaminase (ALT), which peaked between 44 IU/L and 141 IU/L and lasted anywhere from several days to 15 weeks. Patients whose ALT rose 1.5-fold above baseline received short-term corticosteroids with no adverse effects. All but one was tapered off. There were two serious adverse events – one elective knee surgery and one case of transient fever, headache, and myalgia at time of infusion.

So far, valrox appears to be long lasting, but “durability is a huge question for any gene therapy approach,” Dr. Pasi said. “The only way to answer it is to follow patients through.”

In hemophilia B, studies indicate that some patients continue expressing factor IX years after a single infusion of gene therapy (N Engl J Med. 2017 Dec 7;377:2215-27).

Two phase 3 trials will further evaluate safety and optimal dosing of valrox, Dr. Pasi said. The GENEr8-1 trial will use the 6 x 10¹³ VG/kg dose and the GENEr8-2 trial will use the 4 x 10¹³ VG/kg dose. Like the pilot study, these trials will exclude patients with inhibitors, but they may include patients with comorbidities such as liver disease, he said.

Valrox was previously known as BMN 270.

The study was sponsored by BioMarin. Dr. Pasi disclosed research funding, consultancy fees, and speaker and advisory relationships with BioMarin. He disclosed ties to many other companies that develop hemophilia therapies.

SOURCE: Pasi KJ et al. ASH 2017 Abstract 603