Hospitalists are key players in improving hospital performance, but they may be overlooking a leading cause of morbidity and mortality, especially among older adults.

Research suggests that at the time of hospital admission, some 20%-50% of all patients are at risk for malnutrition or are malnourished, but only 7% of those patients are diagnosed during their stay, according to research cited in an abstract presented at HM17.¹

“Because individuals who are malnourished lack sufficient nutrients to promote healing and rehabilitation, and are at increased risk of medical complications, it can have a serious impact on patient safety indicators, such as rates of pressure ulcers, wound healing, and risk of falls,” said lead author Eleanor Fitall of Avalere Health. “Early identification and subsequent treatment of these patients is the best way to prevent this risk.”

To address the issue, Avalere Health and the Academy of Nutrition and Dietetics established the Malnutrition Quality Improvement Initiative (MQii), a multi-stakeholder effort to identify tools to support hospital-based care teams in improving malnutrition care quality. They developed a malnutrition Toolkit, which was piloted in 2016 and was shown to effectively improve malnutrition care.

“Since the poster presentation in May, we have successfully implemented the Toolkit at 50 hospitals via a multi-hospital Learning Collaborative,” Ms. Fitall said. They are now recruiting hospitals and health systems to participate in an expanded Learning Collaborative. Interested sites should contact the MQii team at [email protected].

“By supporting efforts to improve malnutrition care in the inpatient setting, hospitalists can help reduce the incidence of these problems as well as decrease rates of readmissions and reduce patient lengths of stay,” Ms. Fitall said. “Hospitalists are critical to addressing malnutrition care gaps in the hospital. Dietitians that have undertaken malnutrition quality improvement projects using the MQii Toolkit have found that they are most successful when hospitalists are actively engaged in the team, particularly when looking to improve the rate of malnutrition diagnosis. Hospitalists are ideally positioned to champion these efforts.”

Support for MQii was provided by Abbott, she said.
 

Reference

1. Fitall E, Bruno M, Jones K, Lynch J, Silver H, Godamunne K, Valladares A, Mitchell K. Malnutrition Care: “Low Hanging Fruit” for Hospitalist Clinical Performance Improvement [abstract]. J Hosp Med. 2017;12(suppl 2).

Hospitalists are key players in improving hospital performance, but they may be overlooking a leading cause of morbidity and mortality, especially among older adults.

Research suggests that at the time of hospital admission, some 20%-50% of all patients are at risk for malnutrition or are malnourished, but only 7% of those patients are diagnosed during their stay, according to research cited in an abstract presented at HM17.¹

“Because individuals who are malnourished lack sufficient nutrients to promote healing and rehabilitation, and are at increased risk of medical complications, it can have a serious impact on patient safety indicators, such as rates of pressure ulcers, wound healing, and risk of falls,” said lead author Eleanor Fitall of Avalere Health. “Early identification and subsequent treatment of these patients is the best way to prevent this risk.”

To address the issue, Avalere Health and the Academy of Nutrition and Dietetics established the Malnutrition Quality Improvement Initiative (MQii), a multi-stakeholder effort to identify tools to support hospital-based care teams in improving malnutrition care quality. They developed a malnutrition Toolkit, which was piloted in 2016 and was shown to effectively improve malnutrition care.

“Since the poster presentation in May, we have successfully implemented the Toolkit at 50 hospitals via a multi-hospital Learning Collaborative,” Ms. Fitall said. They are now recruiting hospitals and health systems to participate in an expanded Learning Collaborative. Interested sites should contact the MQii team at [email protected].

“By supporting efforts to improve malnutrition care in the inpatient setting, hospitalists can help reduce the incidence of these problems as well as decrease rates of readmissions and reduce patient lengths of stay,” Ms. Fitall said. “Hospitalists are critical to addressing malnutrition care gaps in the hospital. Dietitians that have undertaken malnutrition quality improvement projects using the MQii Toolkit have found that they are most successful when hospitalists are actively engaged in the team, particularly when looking to improve the rate of malnutrition diagnosis. Hospitalists are ideally positioned to champion these efforts.”

Support for MQii was provided by Abbott, she said.
 

Reference

1. Fitall E, Bruno M, Jones K, Lynch J, Silver H, Godamunne K, Valladares A, Mitchell K. Malnutrition Care: “Low Hanging Fruit” for Hospitalist Clinical Performance Improvement [abstract]. J Hosp Med. 2017;12(suppl 2).

Hospitalists are key players in improving hospital performance, but they may be overlooking a leading cause of morbidity and mortality, especially among older adults.

Research suggests that at the time of hospital admission, some 20%-50% of all patients are at risk for malnutrition or are malnourished, but only 7% of those patients are diagnosed during their stay, according to research cited in an abstract presented at HM17.¹

“Because individuals who are malnourished lack sufficient nutrients to promote healing and rehabilitation, and are at increased risk of medical complications, it can have a serious impact on patient safety indicators, such as rates of pressure ulcers, wound healing, and risk of falls,” said lead author Eleanor Fitall of Avalere Health. “Early identification and subsequent treatment of these patients is the best way to prevent this risk.”

To address the issue, Avalere Health and the Academy of Nutrition and Dietetics established the Malnutrition Quality Improvement Initiative (MQii), a multi-stakeholder effort to identify tools to support hospital-based care teams in improving malnutrition care quality. They developed a malnutrition Toolkit, which was piloted in 2016 and was shown to effectively improve malnutrition care.

“Since the poster presentation in May, we have successfully implemented the Toolkit at 50 hospitals via a multi-hospital Learning Collaborative,” Ms. Fitall said. They are now recruiting hospitals and health systems to participate in an expanded Learning Collaborative. Interested sites should contact the MQii team at [email protected].

“By supporting efforts to improve malnutrition care in the inpatient setting, hospitalists can help reduce the incidence of these problems as well as decrease rates of readmissions and reduce patient lengths of stay,” Ms. Fitall said. “Hospitalists are critical to addressing malnutrition care gaps in the hospital. Dietitians that have undertaken malnutrition quality improvement projects using the MQii Toolkit have found that they are most successful when hospitalists are actively engaged in the team, particularly when looking to improve the rate of malnutrition diagnosis. Hospitalists are ideally positioned to champion these efforts.”

Support for MQii was provided by Abbott, she said.
 

Reference

1. Fitall E, Bruno M, Jones K, Lynch J, Silver H, Godamunne K, Valladares A, Mitchell K. Malnutrition Care: “Low Hanging Fruit” for Hospitalist Clinical Performance Improvement [abstract]. J Hosp Med. 2017;12(suppl 2).

A new study finds that two nearly ubiquitous herpes viruses, HHV-6a and HHV-7, are abundant in the brains of people with Alzheimer’s disease. Also today, midlife retinopathy predicts ischemic stroke, fingernails may hold a clue for relapsing scabies, and canakinumab cuts gout attacks by nearly half.

Listen to the MDedge Daily News podcast for all the details on today’s top news.


 

A new study finds that two nearly ubiquitous herpes viruses, HHV-6a and HHV-7, are abundant in the brains of people with Alzheimer’s disease. Also today, midlife retinopathy predicts ischemic stroke, fingernails may hold a clue for relapsing scabies, and canakinumab cuts gout attacks by nearly half.

Listen to the MDedge Daily News podcast for all the details on today’s top news.


 

A new study finds that two nearly ubiquitous herpes viruses, HHV-6a and HHV-7, are abundant in the brains of people with Alzheimer’s disease. Also today, midlife retinopathy predicts ischemic stroke, fingernails may hold a clue for relapsing scabies, and canakinumab cuts gout attacks by nearly half.

Listen to the MDedge Daily News podcast for all the details on today’s top news.


 

Cryptococcal meningitis is one of the most common mycoses in patients with HIV/AIDS. In developed countries, mortality rates due to the disease hover around 9%—in poor and underdeveloped regions, the number leaps to 70%. Many of those deaths are related to lack of access and difficulty in administering amphotericin B and  flucytosine. That is the most effective standard treatment, but it is expensive and carries serious adverse effects, including nephrotoxicity, hepatotoxicity, and bone marrow suppression. Fluconazole, also commonly used, does not effectively clear fungal burden and is associated with clinical relapse.

More antifungals are desperately needed, but it takes billions of dollars to get a drug to market, and the process is slow. Where are the new antifungals to come from?  Maybe from other drugs?

Researchers have begun mining drug compound “libraries,” searching for existing drugs that can be repurposed. The drugs have already passed all the regulatory hurdles—it is just a matter of finding which ones could be turned to a new use. The antidepressant sertraline, for instance, has been found to be a potent antifungal that works synergistically with fluconazole and is now being repurposed for cryptococcal meningitis. 

Researchers from University of Technology Sydney screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth of Cryptococcus deuterogattii. The search turned up promising results for the anthelminthic agent flubendazole, as well as the L-type calcium channel blockers nifedipine, nisoldipine, and felodipine. Flubendazole was very active against all pathogenic Cryptococcus species, and, importantly, was equally effective against isolates resistant to fluconazole. Nifedipine, nisoldipine and felodipine inhibited Cryptococcus. Nisoldipine was also effective against Candida, Saccharomyces and Aspergillus.

The researchers say flubendazole may be the best starting point for treating cryptococcal disease, both for its effectiveness and because research has not found serious adverse effects from antihelminthic treatment. Flubendazole interferes with normal cell growth as early as 3 hours posttreatment and continues to render treated Cryptococcus cells unviable. However, because flubendazole is formulated to treat gastrointestinal worms, it is not yet known whether it would be able to reach therapeutic concentrations in the brain required for an antifungal effect.

Overall, their findings, the researchers say, “validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.”

Source:
Truong M, Monahan LG, Carter DA, Charles IG. PeerJ. 2018;6: e4761.
doi: 10.7717/peerj.4761

Cryptococcal meningitis is one of the most common mycoses in patients with HIV/AIDS. In developed countries, mortality rates due to the disease hover around 9%—in poor and underdeveloped regions, the number leaps to 70%. Many of those deaths are related to lack of access and difficulty in administering amphotericin B and  flucytosine. That is the most effective standard treatment, but it is expensive and carries serious adverse effects, including nephrotoxicity, hepatotoxicity, and bone marrow suppression. Fluconazole, also commonly used, does not effectively clear fungal burden and is associated with clinical relapse.

More antifungals are desperately needed, but it takes billions of dollars to get a drug to market, and the process is slow. Where are the new antifungals to come from?  Maybe from other drugs?

Researchers have begun mining drug compound “libraries,” searching for existing drugs that can be repurposed. The drugs have already passed all the regulatory hurdles—it is just a matter of finding which ones could be turned to a new use. The antidepressant sertraline, for instance, has been found to be a potent antifungal that works synergistically with fluconazole and is now being repurposed for cryptococcal meningitis. 

Researchers from University of Technology Sydney screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth of Cryptococcus deuterogattii. The search turned up promising results for the anthelminthic agent flubendazole, as well as the L-type calcium channel blockers nifedipine, nisoldipine, and felodipine. Flubendazole was very active against all pathogenic Cryptococcus species, and, importantly, was equally effective against isolates resistant to fluconazole. Nifedipine, nisoldipine and felodipine inhibited Cryptococcus. Nisoldipine was also effective against Candida, Saccharomyces and Aspergillus.

The researchers say flubendazole may be the best starting point for treating cryptococcal disease, both for its effectiveness and because research has not found serious adverse effects from antihelminthic treatment. Flubendazole interferes with normal cell growth as early as 3 hours posttreatment and continues to render treated Cryptococcus cells unviable. However, because flubendazole is formulated to treat gastrointestinal worms, it is not yet known whether it would be able to reach therapeutic concentrations in the brain required for an antifungal effect.

Overall, their findings, the researchers say, “validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.”

Source:
Truong M, Monahan LG, Carter DA, Charles IG. PeerJ. 2018;6: e4761.
doi: 10.7717/peerj.4761

Cryptococcal meningitis is one of the most common mycoses in patients with HIV/AIDS. In developed countries, mortality rates due to the disease hover around 9%—in poor and underdeveloped regions, the number leaps to 70%. Many of those deaths are related to lack of access and difficulty in administering amphotericin B and  flucytosine. That is the most effective standard treatment, but it is expensive and carries serious adverse effects, including nephrotoxicity, hepatotoxicity, and bone marrow suppression. Fluconazole, also commonly used, does not effectively clear fungal burden and is associated with clinical relapse.

More antifungals are desperately needed, but it takes billions of dollars to get a drug to market, and the process is slow. Where are the new antifungals to come from?  Maybe from other drugs?

Researchers have begun mining drug compound “libraries,” searching for existing drugs that can be repurposed. The drugs have already passed all the regulatory hurdles—it is just a matter of finding which ones could be turned to a new use. The antidepressant sertraline, for instance, has been found to be a potent antifungal that works synergistically with fluconazole and is now being repurposed for cryptococcal meningitis. 

Researchers from University of Technology Sydney screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth of Cryptococcus deuterogattii. The search turned up promising results for the anthelminthic agent flubendazole, as well as the L-type calcium channel blockers nifedipine, nisoldipine, and felodipine. Flubendazole was very active against all pathogenic Cryptococcus species, and, importantly, was equally effective against isolates resistant to fluconazole. Nifedipine, nisoldipine and felodipine inhibited Cryptococcus. Nisoldipine was also effective against Candida, Saccharomyces and Aspergillus.

The researchers say flubendazole may be the best starting point for treating cryptococcal disease, both for its effectiveness and because research has not found serious adverse effects from antihelminthic treatment. Flubendazole interferes with normal cell growth as early as 3 hours posttreatment and continues to render treated Cryptococcus cells unviable. However, because flubendazole is formulated to treat gastrointestinal worms, it is not yet known whether it would be able to reach therapeutic concentrations in the brain required for an antifungal effect.

Overall, their findings, the researchers say, “validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.”

Source:
Truong M, Monahan LG, Carter DA, Charles IG. PeerJ. 2018;6: e4761.
doi: 10.7717/peerj.4761

Photo from EHA

STOCKHOLM—Results of a phase 3 study suggest the long-acting C5 complement inhibitor ravulizumab produces similar results as eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH).

Treatment with ravulizumab every 8 weeks proved noninferior to treatment with eculizumab every 2 weeks for the co-primary endpoints of transfusion avoidance and hemolysis as measured by lactate dehydrogenase (LDH) normalization.

Ravulizumab also proved noninferior with regard to secondary efficacy endpoints and had a safety profile similar to that of eculizumab.

These results suggest ravulizumab could be a more convenient alternative for PNH patients, according to Jong Wook Lee, MD, of Seoul St. Mary’s Hospital in Seoul, South Korea.

Dr Lee presented these results as a late-breaking abstract (LB2603) at the 23rd Congress of the European Hematology Association (EHA).

The study was sponsored by Alexion Pharmaceuticals.

The trial enrolled adults with PNH naive to complement inhibitor therapy. They were randomized to receive ravulizumab (n=125) or eculizumab (n=121) for 183 days.

More than half of patients were male—52% in the ravulizumab arm and 57% in the eculizumab arm.  Most patients were Asian (57.6% in the ravulizumab arm and 47.1% in the eculizumab arm) or white (34.4% and 42.1%, respectively).

Patients’ mean age at first infusion was 44.8 in the ravulizumab arm and 46.2 in the eculizumab arm. The mean number of years from PNH diagnosis to consent was 6.7 and 6.4, respectively.

The mean LDH at baseline was 1634 U/L in the ravulizumab arm and 1578 U/L in the eculizumab arm. The mean FACIT-Fatigue score was 36.7 and 36.9, respectively.

All 125 ravulizumab patients completed 26 weeks of treatment, as did 119 of the eculizumab patients. One hundred twenty-four ravulizumab patients entered the extension phase, as did 119 eculizumab patients.

Efficacy

The study’s primary efficacy endpoints were transfusion avoidance and LDH normalization from day 29 to 183. Dr Lee said ravulizumab proved noninferior to eculizumab for both endpoints, and point estimates favored ravulizumab.

The proportion of patients who remained transfusion-free was 73.6% in the ravulizumab arm and 66.1% in the eculizumab arm (difference, 6.8; 95% CI, -4.66, 18.14).

The proportion of patients who achieved LDH normalization was 53.6% and 49.4%, respectively (difference, 1.19; 95% CI, 0.8, 1.77).

Secondary efficacy endpoints included the percentage change in LDH from baseline, change in FACIT-Fatigue score from baseline, and the proportions of patients with breakthrough hemolysis and stabilized hemoglobin.

Again, ravulizumab was noninferior to eculizumab for all endpoints, with point estimates favoring ravulizumab.

The LDH percentage change was -76.84% in the ravulizumab arm and -76.02% in the eculizumab arm (difference, 0.83; 95% CI, -3.56, 5.21).

The change (improvement) in FACIT-Fatigue score was 7.07 and 6.40, respectively (difference, 0.67; 95% CI, -1.21, 2.55).

The percentage of patients with hemoglobin stabilization was 68.0% in the ravulizumab arm and 64.5% in the eculizumab arm (difference, 2.9; 95% CI, -8.80, 14.64).

The percentage of patients with breakthrough hemolysis was 4.0% and 10.7%, respectively (difference, 6.7; 95% CI, -0.18, 14.21).

Dr Lee noted that the proportion of patients with breakthrough hemolysis was more than 2.5-fold higher in the eculizumab arm than the ravulizumab arm—13 patients with 15 events and 5 patients with 5 events, respectively.

He said this was likely due to the immediate, complete, and sustained inhibition of C5 (mean free C5 <0.5 μg/mL) achieved by ravulizumab. Complete inhibition was observed after the first ravulizumab infusion and was sustained throughout the 26-week treatment period.

Safety

Dr Lee said ravulizumab had a similar safety profile to eculizumab, and both drugs were well tolerated.

Most patients experienced a treatment-emergent adverse event (TEAE)—88% in the ravulizumab arm and 86.8% in the eculizumab arm.

The most common TEAEs (in the ravulizumab and eculizumab arms, respectively) were headache (36.0% and 33.1%), nasopharyngitis (8.8% and 14.9%), upper respiratory tract infection (10.4% and 5.8%), and pyrexia (4.8% and 10.7%).

Serious AEs occurred in 8.8% of patients in the ravulizumab arm and 7.4% of those in the eculizumab arm.

Major adverse vascular events occurred in 2 patients in the ravulizumab arm and 1 in the eculizumab arm. There were no meningococcal infections in either arm.

One patient in the eculizumab arm was discontinued from the study and died of lung cancer (which was unrelated to treatment).

Photo from EHA

STOCKHOLM—Results of a phase 3 study suggest the long-acting C5 complement inhibitor ravulizumab produces similar results as eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH).

Treatment with ravulizumab every 8 weeks proved noninferior to treatment with eculizumab every 2 weeks for the co-primary endpoints of transfusion avoidance and hemolysis as measured by lactate dehydrogenase (LDH) normalization.

Ravulizumab also proved noninferior with regard to secondary efficacy endpoints and had a safety profile similar to that of eculizumab.

These results suggest ravulizumab could be a more convenient alternative for PNH patients, according to Jong Wook Lee, MD, of Seoul St. Mary’s Hospital in Seoul, South Korea.

Dr Lee presented these results as a late-breaking abstract (LB2603) at the 23rd Congress of the European Hematology Association (EHA).

The study was sponsored by Alexion Pharmaceuticals.

The trial enrolled adults with PNH naive to complement inhibitor therapy. They were randomized to receive ravulizumab (n=125) or eculizumab (n=121) for 183 days.

More than half of patients were male—52% in the ravulizumab arm and 57% in the eculizumab arm.  Most patients were Asian (57.6% in the ravulizumab arm and 47.1% in the eculizumab arm) or white (34.4% and 42.1%, respectively).

Patients’ mean age at first infusion was 44.8 in the ravulizumab arm and 46.2 in the eculizumab arm. The mean number of years from PNH diagnosis to consent was 6.7 and 6.4, respectively.

The mean LDH at baseline was 1634 U/L in the ravulizumab arm and 1578 U/L in the eculizumab arm. The mean FACIT-Fatigue score was 36.7 and 36.9, respectively.

All 125 ravulizumab patients completed 26 weeks of treatment, as did 119 of the eculizumab patients. One hundred twenty-four ravulizumab patients entered the extension phase, as did 119 eculizumab patients.

Efficacy

The study’s primary efficacy endpoints were transfusion avoidance and LDH normalization from day 29 to 183. Dr Lee said ravulizumab proved noninferior to eculizumab for both endpoints, and point estimates favored ravulizumab.

The proportion of patients who remained transfusion-free was 73.6% in the ravulizumab arm and 66.1% in the eculizumab arm (difference, 6.8; 95% CI, -4.66, 18.14).

The proportion of patients who achieved LDH normalization was 53.6% and 49.4%, respectively (difference, 1.19; 95% CI, 0.8, 1.77).

Secondary efficacy endpoints included the percentage change in LDH from baseline, change in FACIT-Fatigue score from baseline, and the proportions of patients with breakthrough hemolysis and stabilized hemoglobin.

Again, ravulizumab was noninferior to eculizumab for all endpoints, with point estimates favoring ravulizumab.

The LDH percentage change was -76.84% in the ravulizumab arm and -76.02% in the eculizumab arm (difference, 0.83; 95% CI, -3.56, 5.21).

The change (improvement) in FACIT-Fatigue score was 7.07 and 6.40, respectively (difference, 0.67; 95% CI, -1.21, 2.55).

The percentage of patients with hemoglobin stabilization was 68.0% in the ravulizumab arm and 64.5% in the eculizumab arm (difference, 2.9; 95% CI, -8.80, 14.64).

The percentage of patients with breakthrough hemolysis was 4.0% and 10.7%, respectively (difference, 6.7; 95% CI, -0.18, 14.21).

Dr Lee noted that the proportion of patients with breakthrough hemolysis was more than 2.5-fold higher in the eculizumab arm than the ravulizumab arm—13 patients with 15 events and 5 patients with 5 events, respectively.

He said this was likely due to the immediate, complete, and sustained inhibition of C5 (mean free C5 <0.5 μg/mL) achieved by ravulizumab. Complete inhibition was observed after the first ravulizumab infusion and was sustained throughout the 26-week treatment period.

Safety

Dr Lee said ravulizumab had a similar safety profile to eculizumab, and both drugs were well tolerated.

Most patients experienced a treatment-emergent adverse event (TEAE)—88% in the ravulizumab arm and 86.8% in the eculizumab arm.

The most common TEAEs (in the ravulizumab and eculizumab arms, respectively) were headache (36.0% and 33.1%), nasopharyngitis (8.8% and 14.9%), upper respiratory tract infection (10.4% and 5.8%), and pyrexia (4.8% and 10.7%).

Serious AEs occurred in 8.8% of patients in the ravulizumab arm and 7.4% of those in the eculizumab arm.

Major adverse vascular events occurred in 2 patients in the ravulizumab arm and 1 in the eculizumab arm. There were no meningococcal infections in either arm.

One patient in the eculizumab arm was discontinued from the study and died of lung cancer (which was unrelated to treatment).

Photo from EHA

STOCKHOLM—Results of a phase 3 study suggest the long-acting C5 complement inhibitor ravulizumab produces similar results as eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH).

Treatment with ravulizumab every 8 weeks proved noninferior to treatment with eculizumab every 2 weeks for the co-primary endpoints of transfusion avoidance and hemolysis as measured by lactate dehydrogenase (LDH) normalization.

Ravulizumab also proved noninferior with regard to secondary efficacy endpoints and had a safety profile similar to that of eculizumab.

These results suggest ravulizumab could be a more convenient alternative for PNH patients, according to Jong Wook Lee, MD, of Seoul St. Mary’s Hospital in Seoul, South Korea.

Dr Lee presented these results as a late-breaking abstract (LB2603) at the 23rd Congress of the European Hematology Association (EHA).

The study was sponsored by Alexion Pharmaceuticals.

The trial enrolled adults with PNH naive to complement inhibitor therapy. They were randomized to receive ravulizumab (n=125) or eculizumab (n=121) for 183 days.

More than half of patients were male—52% in the ravulizumab arm and 57% in the eculizumab arm.  Most patients were Asian (57.6% in the ravulizumab arm and 47.1% in the eculizumab arm) or white (34.4% and 42.1%, respectively).

Patients’ mean age at first infusion was 44.8 in the ravulizumab arm and 46.2 in the eculizumab arm. The mean number of years from PNH diagnosis to consent was 6.7 and 6.4, respectively.

The mean LDH at baseline was 1634 U/L in the ravulizumab arm and 1578 U/L in the eculizumab arm. The mean FACIT-Fatigue score was 36.7 and 36.9, respectively.

All 125 ravulizumab patients completed 26 weeks of treatment, as did 119 of the eculizumab patients. One hundred twenty-four ravulizumab patients entered the extension phase, as did 119 eculizumab patients.

Efficacy

The study’s primary efficacy endpoints were transfusion avoidance and LDH normalization from day 29 to 183. Dr Lee said ravulizumab proved noninferior to eculizumab for both endpoints, and point estimates favored ravulizumab.

The proportion of patients who remained transfusion-free was 73.6% in the ravulizumab arm and 66.1% in the eculizumab arm (difference, 6.8; 95% CI, -4.66, 18.14).

The proportion of patients who achieved LDH normalization was 53.6% and 49.4%, respectively (difference, 1.19; 95% CI, 0.8, 1.77).

Secondary efficacy endpoints included the percentage change in LDH from baseline, change in FACIT-Fatigue score from baseline, and the proportions of patients with breakthrough hemolysis and stabilized hemoglobin.

Again, ravulizumab was noninferior to eculizumab for all endpoints, with point estimates favoring ravulizumab.

The LDH percentage change was -76.84% in the ravulizumab arm and -76.02% in the eculizumab arm (difference, 0.83; 95% CI, -3.56, 5.21).

The change (improvement) in FACIT-Fatigue score was 7.07 and 6.40, respectively (difference, 0.67; 95% CI, -1.21, 2.55).

The percentage of patients with hemoglobin stabilization was 68.0% in the ravulizumab arm and 64.5% in the eculizumab arm (difference, 2.9; 95% CI, -8.80, 14.64).

The percentage of patients with breakthrough hemolysis was 4.0% and 10.7%, respectively (difference, 6.7; 95% CI, -0.18, 14.21).

Dr Lee noted that the proportion of patients with breakthrough hemolysis was more than 2.5-fold higher in the eculizumab arm than the ravulizumab arm—13 patients with 15 events and 5 patients with 5 events, respectively.

He said this was likely due to the immediate, complete, and sustained inhibition of C5 (mean free C5 <0.5 μg/mL) achieved by ravulizumab. Complete inhibition was observed after the first ravulizumab infusion and was sustained throughout the 26-week treatment period.

Safety

Dr Lee said ravulizumab had a similar safety profile to eculizumab, and both drugs were well tolerated.

Most patients experienced a treatment-emergent adverse event (TEAE)—88% in the ravulizumab arm and 86.8% in the eculizumab arm.

The most common TEAEs (in the ravulizumab and eculizumab arms, respectively) were headache (36.0% and 33.1%), nasopharyngitis (8.8% and 14.9%), upper respiratory tract infection (10.4% and 5.8%), and pyrexia (4.8% and 10.7%).

Serious AEs occurred in 8.8% of patients in the ravulizumab arm and 7.4% of those in the eculizumab arm.

Major adverse vascular events occurred in 2 patients in the ravulizumab arm and 1 in the eculizumab arm. There were no meningococcal infections in either arm.

One patient in the eculizumab arm was discontinued from the study and died of lung cancer (which was unrelated to treatment).

Amandeep Salhotra, MD

STOCKHOLM—The ROCK2 inhibitor KD025 produced responses in about two-thirds of patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2 trial.

KD025 elicited improvements in Lee Symptom Scale score, and patients were able to reduce doses of corticosteroids and other immunosuppressants.

There were no serious adverse events (AEs) related to KD025 and no apparent increased risk of infection with the drug.

Amandeep Salhotra, MD, of City of Hope in Duarte, California, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S873. The research was sponsored by Kadmon Holdings, Inc.

This ongoing phase 2 trial has enrolled 48 adults with steroid-dependent or steroid-refractory cGVHD and active disease.

The patients were divided into 3 cohorts, in which they received different dose levels of KD025—200 mg daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg daily (cohort 3).

Dr Salhotra presented results in cohorts 1 (n=17) and 2 (n=16). These patients had cGVHD for a median of 18.9 months before enrollment and had received a median of 3 prior lines of cGVHD therapy. They had cGVHD involvement across all organ systems.

The median age was 50 (range, 20-63) in cohort 1 and 55 (range, 30-75) in cohort 2. The median time to cGHVD diagnosis was 9.1 months in cohort 1 and 7.7 months in cohort 2. The median time from cGVHD diagnosis to enrollment was 25.9 months and 15.8 months, respectively.

All patients in cohort 1 had at least 2 organs involved, as did 94% of patients in cohort 2. Forty-seven percent and 69%, respectively, had at least 4 organs involved.

Treatment duration

The median treatment duration was 37 weeks in cohort 1 and 33 weeks in cohort 2. Four patients in cohort 1 had cGVHD progression, as did 8 patients in cohort 2.

Seven patients in cohort 1 withdrew from the study—2 due to cancer relapse, 2 due to AEs (headache and diarrhea), 1 due to investigator decision, and 2 due to voluntary withdrawal. Three patients in cohort 2 withdrew—1 due to investigator decision and 2 due to voluntary withdrawal.

Six patients are still active in cohort 1, with a median treatment duration of 70 weeks. Five patients are still active in cohort 2, with a median treatment duration of 58 weeks.

Safety

“The adverse events were, overall, consistent with those expected in patients with chronic GVHD receiving corticosteroids,” Dr Salhotra said. “There were no treatment-related serious adverse events, and there was no increased signal of infection.”

Ninety-four percent of patients in both cohorts had AEs. Thirty-five percent of patients in cohort 1 and 63% in cohort 2 had treatment-related AEs. Twelve percent and 31%, respectively, had grade 3 or higher related AEs. Twelve percent of patients in cohort 1 had a related AE leading to discontinuation (2 events, headache and diarrhea).

Commonly reported AEs (in cohorts 1 and 2, respectively) included ALT/AST elevation (35% and 25%), upper respiratory tract infection (24% and 38%), anemia (29% and 25%), gamma-glutamyltransferase elevation (24% and 31%), diarrhea (35% and 13%), and nausea (35% and 13%).

Response

The overall response rate (ORR) was 65% (11/17) in cohort 1 and 69% (11/16) in cohort 2.

In patients with at least 2 prior lines of systemic therapy, the ORR was 65% (11/17) in cohort 1 and 64% (9/14) in cohort 2. In patients with severe cGVHD, the ORR was 67% (8/12) in cohort 1 and 64% (9/14) in cohort 2.

“Responses were rapid,” Dr Salhotra noted. “Seventy-seven percent of the responders achieved a response by the time of first assessment, which was at 8 weeks.”

“These responses were durable. Seventy-three percent (8/11) of responders in cohort 1 and 55% (6/11) of responders in cohort 2 have sustained responses for more than 20 weeks. At the 32-week endpoint, there were 45% (5/11) responders in cohort 1 and 18% (2/11) in cohort 2.”

Dr Salhotra added that responses were observed across all affected organ systems, including complete responses in upper and lower gastrointestinal systems, mouth, joints/fascia, skin, eyes, and liver.

Of the 13 responders in cohorts 1 and 2 with at least 4 organs involved, 46% (n=6) achieved responses in 4 or more organs.

In cohort 1, 73% (8/11) of responders and 83% (5/6) of non-responders had corticosteroid dose reductions. In cohort 2, 55% (6/11) of responders and 60% (3/5) of non-responders had dose reductions.

Five patients have completely discontinued steroids—4 (24%) in cohort 1 and 1 (6%) in cohort 2.

There were 6 patients each in cohorts 1 and 2 who were receiving tacrolimus. Each cohort had 5 patients (83%) who had tacrolimus dose reductions on KD025. One patient completely discontinued tacrolimus.

Sixty-five percent of patients in cohort 1 and 44% in cohort 2 had a clinically meaningful improvement in cGVHD symptoms, which was defined as at least a 7-point decrease in the Lee Symptom Scale score. Both responders and non-responders had such improvements.

Based on these results, Kadmon Holdings, Inc., is planning a pivotal study of KD025 in cGVHD, which is expected to begin in the third quarter of 2018.

Dr Salhotra said the study will enroll adults who have received at least 2 prior lines of systemic therapy for cGVHD. Patients will be randomized to receive KD025 at 200 mg daily or 200 mg twice daily. The primary endpoint will be ORR.

Amandeep Salhotra, MD

STOCKHOLM—The ROCK2 inhibitor KD025 produced responses in about two-thirds of patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2 trial.

KD025 elicited improvements in Lee Symptom Scale score, and patients were able to reduce doses of corticosteroids and other immunosuppressants.

There were no serious adverse events (AEs) related to KD025 and no apparent increased risk of infection with the drug.

Amandeep Salhotra, MD, of City of Hope in Duarte, California, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S873. The research was sponsored by Kadmon Holdings, Inc.

This ongoing phase 2 trial has enrolled 48 adults with steroid-dependent or steroid-refractory cGVHD and active disease.

The patients were divided into 3 cohorts, in which they received different dose levels of KD025—200 mg daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg daily (cohort 3).

Dr Salhotra presented results in cohorts 1 (n=17) and 2 (n=16). These patients had cGVHD for a median of 18.9 months before enrollment and had received a median of 3 prior lines of cGVHD therapy. They had cGVHD involvement across all organ systems.

The median age was 50 (range, 20-63) in cohort 1 and 55 (range, 30-75) in cohort 2. The median time to cGHVD diagnosis was 9.1 months in cohort 1 and 7.7 months in cohort 2. The median time from cGVHD diagnosis to enrollment was 25.9 months and 15.8 months, respectively.

All patients in cohort 1 had at least 2 organs involved, as did 94% of patients in cohort 2. Forty-seven percent and 69%, respectively, had at least 4 organs involved.

Treatment duration

The median treatment duration was 37 weeks in cohort 1 and 33 weeks in cohort 2. Four patients in cohort 1 had cGVHD progression, as did 8 patients in cohort 2.

Seven patients in cohort 1 withdrew from the study—2 due to cancer relapse, 2 due to AEs (headache and diarrhea), 1 due to investigator decision, and 2 due to voluntary withdrawal. Three patients in cohort 2 withdrew—1 due to investigator decision and 2 due to voluntary withdrawal.

Six patients are still active in cohort 1, with a median treatment duration of 70 weeks. Five patients are still active in cohort 2, with a median treatment duration of 58 weeks.

Safety

“The adverse events were, overall, consistent with those expected in patients with chronic GVHD receiving corticosteroids,” Dr Salhotra said. “There were no treatment-related serious adverse events, and there was no increased signal of infection.”

Ninety-four percent of patients in both cohorts had AEs. Thirty-five percent of patients in cohort 1 and 63% in cohort 2 had treatment-related AEs. Twelve percent and 31%, respectively, had grade 3 or higher related AEs. Twelve percent of patients in cohort 1 had a related AE leading to discontinuation (2 events, headache and diarrhea).

Commonly reported AEs (in cohorts 1 and 2, respectively) included ALT/AST elevation (35% and 25%), upper respiratory tract infection (24% and 38%), anemia (29% and 25%), gamma-glutamyltransferase elevation (24% and 31%), diarrhea (35% and 13%), and nausea (35% and 13%).

Response

The overall response rate (ORR) was 65% (11/17) in cohort 1 and 69% (11/16) in cohort 2.

In patients with at least 2 prior lines of systemic therapy, the ORR was 65% (11/17) in cohort 1 and 64% (9/14) in cohort 2. In patients with severe cGVHD, the ORR was 67% (8/12) in cohort 1 and 64% (9/14) in cohort 2.

“Responses were rapid,” Dr Salhotra noted. “Seventy-seven percent of the responders achieved a response by the time of first assessment, which was at 8 weeks.”

“These responses were durable. Seventy-three percent (8/11) of responders in cohort 1 and 55% (6/11) of responders in cohort 2 have sustained responses for more than 20 weeks. At the 32-week endpoint, there were 45% (5/11) responders in cohort 1 and 18% (2/11) in cohort 2.”

Dr Salhotra added that responses were observed across all affected organ systems, including complete responses in upper and lower gastrointestinal systems, mouth, joints/fascia, skin, eyes, and liver.

Of the 13 responders in cohorts 1 and 2 with at least 4 organs involved, 46% (n=6) achieved responses in 4 or more organs.

In cohort 1, 73% (8/11) of responders and 83% (5/6) of non-responders had corticosteroid dose reductions. In cohort 2, 55% (6/11) of responders and 60% (3/5) of non-responders had dose reductions.

Five patients have completely discontinued steroids—4 (24%) in cohort 1 and 1 (6%) in cohort 2.

There were 6 patients each in cohorts 1 and 2 who were receiving tacrolimus. Each cohort had 5 patients (83%) who had tacrolimus dose reductions on KD025. One patient completely discontinued tacrolimus.

Sixty-five percent of patients in cohort 1 and 44% in cohort 2 had a clinically meaningful improvement in cGVHD symptoms, which was defined as at least a 7-point decrease in the Lee Symptom Scale score. Both responders and non-responders had such improvements.

Based on these results, Kadmon Holdings, Inc., is planning a pivotal study of KD025 in cGVHD, which is expected to begin in the third quarter of 2018.

Dr Salhotra said the study will enroll adults who have received at least 2 prior lines of systemic therapy for cGVHD. Patients will be randomized to receive KD025 at 200 mg daily or 200 mg twice daily. The primary endpoint will be ORR.

Amandeep Salhotra, MD

STOCKHOLM—The ROCK2 inhibitor KD025 produced responses in about two-thirds of patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2 trial.

KD025 elicited improvements in Lee Symptom Scale score, and patients were able to reduce doses of corticosteroids and other immunosuppressants.

There were no serious adverse events (AEs) related to KD025 and no apparent increased risk of infection with the drug.

Amandeep Salhotra, MD, of City of Hope in Duarte, California, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S873. The research was sponsored by Kadmon Holdings, Inc.

This ongoing phase 2 trial has enrolled 48 adults with steroid-dependent or steroid-refractory cGVHD and active disease.

The patients were divided into 3 cohorts, in which they received different dose levels of KD025—200 mg daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg daily (cohort 3).

Dr Salhotra presented results in cohorts 1 (n=17) and 2 (n=16). These patients had cGVHD for a median of 18.9 months before enrollment and had received a median of 3 prior lines of cGVHD therapy. They had cGVHD involvement across all organ systems.

The median age was 50 (range, 20-63) in cohort 1 and 55 (range, 30-75) in cohort 2. The median time to cGHVD diagnosis was 9.1 months in cohort 1 and 7.7 months in cohort 2. The median time from cGVHD diagnosis to enrollment was 25.9 months and 15.8 months, respectively.

All patients in cohort 1 had at least 2 organs involved, as did 94% of patients in cohort 2. Forty-seven percent and 69%, respectively, had at least 4 organs involved.

Treatment duration

The median treatment duration was 37 weeks in cohort 1 and 33 weeks in cohort 2. Four patients in cohort 1 had cGVHD progression, as did 8 patients in cohort 2.

Seven patients in cohort 1 withdrew from the study—2 due to cancer relapse, 2 due to AEs (headache and diarrhea), 1 due to investigator decision, and 2 due to voluntary withdrawal. Three patients in cohort 2 withdrew—1 due to investigator decision and 2 due to voluntary withdrawal.

Six patients are still active in cohort 1, with a median treatment duration of 70 weeks. Five patients are still active in cohort 2, with a median treatment duration of 58 weeks.

Safety

“The adverse events were, overall, consistent with those expected in patients with chronic GVHD receiving corticosteroids,” Dr Salhotra said. “There were no treatment-related serious adverse events, and there was no increased signal of infection.”

Ninety-four percent of patients in both cohorts had AEs. Thirty-five percent of patients in cohort 1 and 63% in cohort 2 had treatment-related AEs. Twelve percent and 31%, respectively, had grade 3 or higher related AEs. Twelve percent of patients in cohort 1 had a related AE leading to discontinuation (2 events, headache and diarrhea).

Commonly reported AEs (in cohorts 1 and 2, respectively) included ALT/AST elevation (35% and 25%), upper respiratory tract infection (24% and 38%), anemia (29% and 25%), gamma-glutamyltransferase elevation (24% and 31%), diarrhea (35% and 13%), and nausea (35% and 13%).

Response

The overall response rate (ORR) was 65% (11/17) in cohort 1 and 69% (11/16) in cohort 2.

In patients with at least 2 prior lines of systemic therapy, the ORR was 65% (11/17) in cohort 1 and 64% (9/14) in cohort 2. In patients with severe cGVHD, the ORR was 67% (8/12) in cohort 1 and 64% (9/14) in cohort 2.

“Responses were rapid,” Dr Salhotra noted. “Seventy-seven percent of the responders achieved a response by the time of first assessment, which was at 8 weeks.”

“These responses were durable. Seventy-three percent (8/11) of responders in cohort 1 and 55% (6/11) of responders in cohort 2 have sustained responses for more than 20 weeks. At the 32-week endpoint, there were 45% (5/11) responders in cohort 1 and 18% (2/11) in cohort 2.”

Dr Salhotra added that responses were observed across all affected organ systems, including complete responses in upper and lower gastrointestinal systems, mouth, joints/fascia, skin, eyes, and liver.

Of the 13 responders in cohorts 1 and 2 with at least 4 organs involved, 46% (n=6) achieved responses in 4 or more organs.

In cohort 1, 73% (8/11) of responders and 83% (5/6) of non-responders had corticosteroid dose reductions. In cohort 2, 55% (6/11) of responders and 60% (3/5) of non-responders had dose reductions.

Five patients have completely discontinued steroids—4 (24%) in cohort 1 and 1 (6%) in cohort 2.

There were 6 patients each in cohorts 1 and 2 who were receiving tacrolimus. Each cohort had 5 patients (83%) who had tacrolimus dose reductions on KD025. One patient completely discontinued tacrolimus.

Sixty-five percent of patients in cohort 1 and 44% in cohort 2 had a clinically meaningful improvement in cGVHD symptoms, which was defined as at least a 7-point decrease in the Lee Symptom Scale score. Both responders and non-responders had such improvements.

Based on these results, Kadmon Holdings, Inc., is planning a pivotal study of KD025 in cGVHD, which is expected to begin in the third quarter of 2018.

Dr Salhotra said the study will enroll adults who have received at least 2 prior lines of systemic therapy for cGVHD. Patients will be randomized to receive KD025 at 200 mg daily or 200 mg twice daily. The primary endpoint will be ORR.

Photo by Daniel Gay

The US Food and Drug Administration (FDA) has approved 2 Grifols blood screening assays—Procleix Ultrio Elite and Procleix WNV.

Procleix WNV is a qualitative in vitro nucleic acid assay for the detection of West Nile virus RNA in plasma and serum of human blood donors.

Procleix Ultrio Elite is a blood screening assay that delivers simultaneous results for human immunodeficiency virus type 1, hepatitis C virus, and hepatitis B virus. It also detects human immunodeficiency virus type 2.

Procleix Ultrio Elite can be used to test pools of plasma composed of up to 96 individual donations from donors of source plasma.

Grifols will begin commercializing the Procleix Ultrio Elite and Procleix WNV assays in the US later this year.

“These FDA approvals demonstrate our ongoing commitment to expand Grifols comprehensive nucleic acid testing (NAT) solutions portfolio to help labs administer NAT,” said Carsten Schroeder, president of Grifols’s Diagnostic Division.

Procleix Ultrio Elite and Procleix WNV will run on the fully automated NAT blood screening platform Procleix Panther system. The device is an integrated NAT system that fully automates all necessary steps to perform Procleix assays, from sample processing through amplification, detection, and data reduction.

“The addition of the Procleix Panther system with these assays will allow blood centers to efficiently screen for infectious diseases on one simple, automated platform while adapting to changes in donation volume and regulatory requirements,” Schroeder said.

Photo by Daniel Gay

The US Food and Drug Administration (FDA) has approved 2 Grifols blood screening assays—Procleix Ultrio Elite and Procleix WNV.

Procleix WNV is a qualitative in vitro nucleic acid assay for the detection of West Nile virus RNA in plasma and serum of human blood donors.

Procleix Ultrio Elite is a blood screening assay that delivers simultaneous results for human immunodeficiency virus type 1, hepatitis C virus, and hepatitis B virus. It also detects human immunodeficiency virus type 2.

Procleix Ultrio Elite can be used to test pools of plasma composed of up to 96 individual donations from donors of source plasma.

Grifols will begin commercializing the Procleix Ultrio Elite and Procleix WNV assays in the US later this year.

“These FDA approvals demonstrate our ongoing commitment to expand Grifols comprehensive nucleic acid testing (NAT) solutions portfolio to help labs administer NAT,” said Carsten Schroeder, president of Grifols’s Diagnostic Division.

Procleix Ultrio Elite and Procleix WNV will run on the fully automated NAT blood screening platform Procleix Panther system. The device is an integrated NAT system that fully automates all necessary steps to perform Procleix assays, from sample processing through amplification, detection, and data reduction.

“The addition of the Procleix Panther system with these assays will allow blood centers to efficiently screen for infectious diseases on one simple, automated platform while adapting to changes in donation volume and regulatory requirements,” Schroeder said.

Photo by Daniel Gay

The US Food and Drug Administration (FDA) has approved 2 Grifols blood screening assays—Procleix Ultrio Elite and Procleix WNV.

Procleix WNV is a qualitative in vitro nucleic acid assay for the detection of West Nile virus RNA in plasma and serum of human blood donors.

Procleix Ultrio Elite is a blood screening assay that delivers simultaneous results for human immunodeficiency virus type 1, hepatitis C virus, and hepatitis B virus. It also detects human immunodeficiency virus type 2.

Procleix Ultrio Elite can be used to test pools of plasma composed of up to 96 individual donations from donors of source plasma.

Grifols will begin commercializing the Procleix Ultrio Elite and Procleix WNV assays in the US later this year.

“These FDA approvals demonstrate our ongoing commitment to expand Grifols comprehensive nucleic acid testing (NAT) solutions portfolio to help labs administer NAT,” said Carsten Schroeder, president of Grifols’s Diagnostic Division.

Procleix Ultrio Elite and Procleix WNV will run on the fully automated NAT blood screening platform Procleix Panther system. The device is an integrated NAT system that fully automates all necessary steps to perform Procleix assays, from sample processing through amplification, detection, and data reduction.

“The addition of the Procleix Panther system with these assays will allow blood centers to efficiently screen for infectious diseases on one simple, automated platform while adapting to changes in donation volume and regulatory requirements,” Schroeder said.

I got a phone call recently from a friend north of me. “Gosh, did you hear about the State of Ohio Board of Pharmacy ransacking a dermatologist’s office?” he asked. Yes, I had heard about it, and explained that the office compounding rule in Ohio, the reason behind this surprise search and practice, was the subject of an active struggle going on at the state and federal level (see “Beware the state pharmacy board,” Dermatology News, June 3, 2016). I also told him that the pharmacy board swooped into that location because the office had registered for a license to mix drugs (defined by the board as altering a prescription drug by mixing, diluting, or combining), and agreed to unannounced inspections – and that while the dermatologist was not fined, there was a list of compliance issues to be met, including recording the lot number of all samples, keeping separate paper records of each time he mixed medications, and the promise of a return visit soon.

I went on to explain that representatives – past presidents and board members – of the Ohio Dermatological Association (accompanied by Lisa Albany, director of state policy at the American Academy of Dermatology’s Washington office) had met with the state pharmacy board and explained how ridiculous these regulations were. It was a frustrating meeting.

Alicia Ault/MDedge News

I got a phone call recently from a friend north of me. “Gosh, did you hear about the State of Ohio Board of Pharmacy ransacking a dermatologist’s office?” he asked. Yes, I had heard about it, and explained that the office compounding rule in Ohio, the reason behind this surprise search and practice, was the subject of an active struggle going on at the state and federal level (see “Beware the state pharmacy board,” Dermatology News, June 3, 2016). I also told him that the pharmacy board swooped into that location because the office had registered for a license to mix drugs (defined by the board as altering a prescription drug by mixing, diluting, or combining), and agreed to unannounced inspections – and that while the dermatologist was not fined, there was a list of compliance issues to be met, including recording the lot number of all samples, keeping separate paper records of each time he mixed medications, and the promise of a return visit soon.

I went on to explain that representatives – past presidents and board members – of the Ohio Dermatological Association (accompanied by Lisa Albany, director of state policy at the American Academy of Dermatology’s Washington office) had met with the state pharmacy board and explained how ridiculous these regulations were. It was a frustrating meeting.

Alicia Ault/MDedge News

I got a phone call recently from a friend north of me. “Gosh, did you hear about the State of Ohio Board of Pharmacy ransacking a dermatologist’s office?” he asked. Yes, I had heard about it, and explained that the office compounding rule in Ohio, the reason behind this surprise search and practice, was the subject of an active struggle going on at the state and federal level (see “Beware the state pharmacy board,” Dermatology News, June 3, 2016). I also told him that the pharmacy board swooped into that location because the office had registered for a license to mix drugs (defined by the board as altering a prescription drug by mixing, diluting, or combining), and agreed to unannounced inspections – and that while the dermatologist was not fined, there was a list of compliance issues to be met, including recording the lot number of all samples, keeping separate paper records of each time he mixed medications, and the promise of a return visit soon.

I went on to explain that representatives – past presidents and board members – of the Ohio Dermatological Association (accompanied by Lisa Albany, director of state policy at the American Academy of Dermatology’s Washington office) had met with the state pharmacy board and explained how ridiculous these regulations were. It was a frustrating meeting.

Alicia Ault/MDedge News

Physicians may finally have some clarity on payment for inpatient administration of 2 chimeric antigen receptor (CAR) T-cell therapies if a proposed rule from the Centers of Medicare & Medicaid Services becomes final.

The agency is seeking to assign ICD-10-PCS codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta; Kite Pharma, acquired by Gilead in October 2017) and tisagenlecleucel (Kymriah; Novartis) in the inpatient setting for fiscal year 2019. It is also considering the creation of a new Medicare Severity-Diagnosis Related Group (MS-DRG) code for procedures involving the use of CAR T-cell therapy drugs.

Stephanie Farnia, director of health policy and strategic relations for the American Society for Blood and Marrow Transplantation, said the proposal demonstrates that CMS is listening to physicians’ concerns about CAR T payments and working to provide a more reasonable framework. “The primary point of significance is that CAR-T care episodes should be assigned to a specific MS-DRG in FY2019, which will give physicians a clearer sense of inpatient reimbursement in advance,” she said in an interview.

Uncertainty about inpatient payment for administration of the 2 approved CAR T therapies (see p. e126) have been a lingering concern of specialists who use, or are interested in using, the therapies. In April 2018, CMS announced payment rates for outpatient administration of the 2 drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.

However, physicians noted at the time that even if the drugs were first administered in the outpatient setting, inpatient care is likely to occur with CAR T-cell therapies because some patients will need to be admitted for monitoring for serious side effects. In such cases, all payments would then become part of the inpatient stay as per CMS’s 3-day payment window rule.

In the most recent payment proposal, CMS stated that its clinical advisers believe that patients receiving treatment with CAR T-cell therapy would have similar clinical characteristics and comorbidities as patients treated with autologous bone marrow transplant therapy, who are currently assigned to MS-DRG 016 Autologous Bone Marrow Transplant with CC/MCC. Therefore, CMS officials said they would suggest ICD-10-PCS procedure codes XW033C3 and XW043C3 to pre-MDC MS-DRG 016. In addition, the agency is proposing to revise the title of MS-DRG 016 to Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy.

The agency emphasized that it invites public comment on alternative payment approaches for CAR T-cell therapies in the context of the pending, new technology add-on payment applications by the CAR-T drugmakers Novartis and Kite Pharma/Gilead. If approved, the technology add-on payments would provide an additional and separate payment equivalent to up to 50% of the product cost plus the MS-DRG payment received for the episode of care.
 

Shifts and realignments in the face of new developments

The CMS announcement is the latest development in the rapidly growing landscape of CAR T-cell therapies. In 2017, the Food and Drug Administration approved tisagenlecleucel for pediatric acute lymphoblastic leukemia and axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma in adults, and in May 2018, the agency expanded the indication for tisagenlecleucel to include adults with relapsed/refractory large B-cell lymphoma.

Further advancements are expected for CAR T-cell therapies in 2018, said Cai Xuan, PhD, senior analyst in oncology and hematology for GlobalData, a data analytics and commercial intelligence firm.

For starters, pharmaceutical companies are now working toward next-generation CAR T-cell therapies that can be mass produced, Dr Xuan noted. At a recent American Association for Cancer Research meeting, for example, the biopharmaceutical company Cellectis presented early clinical data in pediatric B-cell acute lymphoblastic leukemia for its off-the-shelf CAR T-cell candidate UCART19. In addition, CRISPR Therapeutics presented preclinical data for one of its off-the-shelf CAR T-cell candidates for multiple myeloma, and the company announced it would apply for approval to start human trials by the end of 2018.

“The trend for 2018 is focused on how to eliminate some of the profitability issues with first-generation CAR Ts because companies realize that manufacturing individualized treatments for each patient is not an ideal business model,” Dr Xuan said in an interview.

More market competition is also in the forecast, particularly from smaller companies, Dr Xuan said. “We are likely to see larger companies acquiring smaller ones once their CAR T technology has matured to a certain point. We have seen it with the Gilead-Kite acquisition and Celgene’s acquisition of Juno Therapeutics. This trend will continue as long as smaller companies are able to develop proprietary next-generation CAR T technologies.”
 

Cost, accessibility, and real-world side effects

The key concerns about the therapies are cost and accessibility, especially for the Medicare population. Cost estimates have put the cost of CAR T-cell therapies as high as $1.5 million per patient and that could make them inaccessible for many.

“There remain unanswered questions about value and cost in older adults,” said Walid F Gellad, MD, codirector for the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh. “There are many life-saving treatments in the medical system that cost much less than this therapy. Presumably, its cost will go down as the indications expand and the experience with creating the CAR T cells improves. At least, one would hope.”

The creation of off-the-shelf, third-party products would help improve accessibility for CAR T-cell therapies and lower cost, said Helen Heslop, MD, director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston. “In the longer term, there’re obviously a lot of people looking at how [the treatments] can be made more accessible. These are the first-generation CAR T [products], and I think there’ll be lots of refinements both to make them more effective and safer and also to use a third-party product to bring the cost of goods down.”

Other lingering unknowns about CAR T-cell therapies include how many patients in real-world clinical practice will have serious side effects, compared with those in trials, and the long-term recurrence rates after therapy use, Dr Gellad noted. He recently proposed in an article that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such therapies until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-4).

The current CAR T-cell therapies are only the beginning, said Dr Richard T Maziarz, MD, a bone marrow transplantation and blood cancer specialist at the Oregon Health and Science University Knight Cancer Institute in Portland. “Genetically engineered cell products are going to explode over the course of the next decade. This is not the end of the line, this is the starting point.”

Disclosures. Dr Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patents from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr Gellad reports grants from Express Scripts.

Physicians may finally have some clarity on payment for inpatient administration of 2 chimeric antigen receptor (CAR) T-cell therapies if a proposed rule from the Centers of Medicare & Medicaid Services becomes final.

The agency is seeking to assign ICD-10-PCS codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta; Kite Pharma, acquired by Gilead in October 2017) and tisagenlecleucel (Kymriah; Novartis) in the inpatient setting for fiscal year 2019. It is also considering the creation of a new Medicare Severity-Diagnosis Related Group (MS-DRG) code for procedures involving the use of CAR T-cell therapy drugs.

Stephanie Farnia, director of health policy and strategic relations for the American Society for Blood and Marrow Transplantation, said the proposal demonstrates that CMS is listening to physicians’ concerns about CAR T payments and working to provide a more reasonable framework. “The primary point of significance is that CAR-T care episodes should be assigned to a specific MS-DRG in FY2019, which will give physicians a clearer sense of inpatient reimbursement in advance,” she said in an interview.

Uncertainty about inpatient payment for administration of the 2 approved CAR T therapies (see p. e126) have been a lingering concern of specialists who use, or are interested in using, the therapies. In April 2018, CMS announced payment rates for outpatient administration of the 2 drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.

However, physicians noted at the time that even if the drugs were first administered in the outpatient setting, inpatient care is likely to occur with CAR T-cell therapies because some patients will need to be admitted for monitoring for serious side effects. In such cases, all payments would then become part of the inpatient stay as per CMS’s 3-day payment window rule.

In the most recent payment proposal, CMS stated that its clinical advisers believe that patients receiving treatment with CAR T-cell therapy would have similar clinical characteristics and comorbidities as patients treated with autologous bone marrow transplant therapy, who are currently assigned to MS-DRG 016 Autologous Bone Marrow Transplant with CC/MCC. Therefore, CMS officials said they would suggest ICD-10-PCS procedure codes XW033C3 and XW043C3 to pre-MDC MS-DRG 016. In addition, the agency is proposing to revise the title of MS-DRG 016 to Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy.

The agency emphasized that it invites public comment on alternative payment approaches for CAR T-cell therapies in the context of the pending, new technology add-on payment applications by the CAR-T drugmakers Novartis and Kite Pharma/Gilead. If approved, the technology add-on payments would provide an additional and separate payment equivalent to up to 50% of the product cost plus the MS-DRG payment received for the episode of care.
 

Shifts and realignments in the face of new developments

The CMS announcement is the latest development in the rapidly growing landscape of CAR T-cell therapies. In 2017, the Food and Drug Administration approved tisagenlecleucel for pediatric acute lymphoblastic leukemia and axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma in adults, and in May 2018, the agency expanded the indication for tisagenlecleucel to include adults with relapsed/refractory large B-cell lymphoma.

Further advancements are expected for CAR T-cell therapies in 2018, said Cai Xuan, PhD, senior analyst in oncology and hematology for GlobalData, a data analytics and commercial intelligence firm.

For starters, pharmaceutical companies are now working toward next-generation CAR T-cell therapies that can be mass produced, Dr Xuan noted. At a recent American Association for Cancer Research meeting, for example, the biopharmaceutical company Cellectis presented early clinical data in pediatric B-cell acute lymphoblastic leukemia for its off-the-shelf CAR T-cell candidate UCART19. In addition, CRISPR Therapeutics presented preclinical data for one of its off-the-shelf CAR T-cell candidates for multiple myeloma, and the company announced it would apply for approval to start human trials by the end of 2018.

“The trend for 2018 is focused on how to eliminate some of the profitability issues with first-generation CAR Ts because companies realize that manufacturing individualized treatments for each patient is not an ideal business model,” Dr Xuan said in an interview.

More market competition is also in the forecast, particularly from smaller companies, Dr Xuan said. “We are likely to see larger companies acquiring smaller ones once their CAR T technology has matured to a certain point. We have seen it with the Gilead-Kite acquisition and Celgene’s acquisition of Juno Therapeutics. This trend will continue as long as smaller companies are able to develop proprietary next-generation CAR T technologies.”
 

Cost, accessibility, and real-world side effects

The key concerns about the therapies are cost and accessibility, especially for the Medicare population. Cost estimates have put the cost of CAR T-cell therapies as high as $1.5 million per patient and that could make them inaccessible for many.

“There remain unanswered questions about value and cost in older adults,” said Walid F Gellad, MD, codirector for the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh. “There are many life-saving treatments in the medical system that cost much less than this therapy. Presumably, its cost will go down as the indications expand and the experience with creating the CAR T cells improves. At least, one would hope.”

The creation of off-the-shelf, third-party products would help improve accessibility for CAR T-cell therapies and lower cost, said Helen Heslop, MD, director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston. “In the longer term, there’re obviously a lot of people looking at how [the treatments] can be made more accessible. These are the first-generation CAR T [products], and I think there’ll be lots of refinements both to make them more effective and safer and also to use a third-party product to bring the cost of goods down.”

Other lingering unknowns about CAR T-cell therapies include how many patients in real-world clinical practice will have serious side effects, compared with those in trials, and the long-term recurrence rates after therapy use, Dr Gellad noted. He recently proposed in an article that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such therapies until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-4).

The current CAR T-cell therapies are only the beginning, said Dr Richard T Maziarz, MD, a bone marrow transplantation and blood cancer specialist at the Oregon Health and Science University Knight Cancer Institute in Portland. “Genetically engineered cell products are going to explode over the course of the next decade. This is not the end of the line, this is the starting point.”

Disclosures. Dr Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patents from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr Gellad reports grants from Express Scripts.

Physicians may finally have some clarity on payment for inpatient administration of 2 chimeric antigen receptor (CAR) T-cell therapies if a proposed rule from the Centers of Medicare & Medicaid Services becomes final.

The agency is seeking to assign ICD-10-PCS codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta; Kite Pharma, acquired by Gilead in October 2017) and tisagenlecleucel (Kymriah; Novartis) in the inpatient setting for fiscal year 2019. It is also considering the creation of a new Medicare Severity-Diagnosis Related Group (MS-DRG) code for procedures involving the use of CAR T-cell therapy drugs.

Stephanie Farnia, director of health policy and strategic relations for the American Society for Blood and Marrow Transplantation, said the proposal demonstrates that CMS is listening to physicians’ concerns about CAR T payments and working to provide a more reasonable framework. “The primary point of significance is that CAR-T care episodes should be assigned to a specific MS-DRG in FY2019, which will give physicians a clearer sense of inpatient reimbursement in advance,” she said in an interview.

Uncertainty about inpatient payment for administration of the 2 approved CAR T therapies (see p. e126) have been a lingering concern of specialists who use, or are interested in using, the therapies. In April 2018, CMS announced payment rates for outpatient administration of the 2 drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.

However, physicians noted at the time that even if the drugs were first administered in the outpatient setting, inpatient care is likely to occur with CAR T-cell therapies because some patients will need to be admitted for monitoring for serious side effects. In such cases, all payments would then become part of the inpatient stay as per CMS’s 3-day payment window rule.

In the most recent payment proposal, CMS stated that its clinical advisers believe that patients receiving treatment with CAR T-cell therapy would have similar clinical characteristics and comorbidities as patients treated with autologous bone marrow transplant therapy, who are currently assigned to MS-DRG 016 Autologous Bone Marrow Transplant with CC/MCC. Therefore, CMS officials said they would suggest ICD-10-PCS procedure codes XW033C3 and XW043C3 to pre-MDC MS-DRG 016. In addition, the agency is proposing to revise the title of MS-DRG 016 to Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy.

The agency emphasized that it invites public comment on alternative payment approaches for CAR T-cell therapies in the context of the pending, new technology add-on payment applications by the CAR-T drugmakers Novartis and Kite Pharma/Gilead. If approved, the technology add-on payments would provide an additional and separate payment equivalent to up to 50% of the product cost plus the MS-DRG payment received for the episode of care.
 

Shifts and realignments in the face of new developments

The CMS announcement is the latest development in the rapidly growing landscape of CAR T-cell therapies. In 2017, the Food and Drug Administration approved tisagenlecleucel for pediatric acute lymphoblastic leukemia and axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma in adults, and in May 2018, the agency expanded the indication for tisagenlecleucel to include adults with relapsed/refractory large B-cell lymphoma.

Further advancements are expected for CAR T-cell therapies in 2018, said Cai Xuan, PhD, senior analyst in oncology and hematology for GlobalData, a data analytics and commercial intelligence firm.

For starters, pharmaceutical companies are now working toward next-generation CAR T-cell therapies that can be mass produced, Dr Xuan noted. At a recent American Association for Cancer Research meeting, for example, the biopharmaceutical company Cellectis presented early clinical data in pediatric B-cell acute lymphoblastic leukemia for its off-the-shelf CAR T-cell candidate UCART19. In addition, CRISPR Therapeutics presented preclinical data for one of its off-the-shelf CAR T-cell candidates for multiple myeloma, and the company announced it would apply for approval to start human trials by the end of 2018.

“The trend for 2018 is focused on how to eliminate some of the profitability issues with first-generation CAR Ts because companies realize that manufacturing individualized treatments for each patient is not an ideal business model,” Dr Xuan said in an interview.

More market competition is also in the forecast, particularly from smaller companies, Dr Xuan said. “We are likely to see larger companies acquiring smaller ones once their CAR T technology has matured to a certain point. We have seen it with the Gilead-Kite acquisition and Celgene’s acquisition of Juno Therapeutics. This trend will continue as long as smaller companies are able to develop proprietary next-generation CAR T technologies.”
 

Cost, accessibility, and real-world side effects

The key concerns about the therapies are cost and accessibility, especially for the Medicare population. Cost estimates have put the cost of CAR T-cell therapies as high as $1.5 million per patient and that could make them inaccessible for many.

“There remain unanswered questions about value and cost in older adults,” said Walid F Gellad, MD, codirector for the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh. “There are many life-saving treatments in the medical system that cost much less than this therapy. Presumably, its cost will go down as the indications expand and the experience with creating the CAR T cells improves. At least, one would hope.”

The creation of off-the-shelf, third-party products would help improve accessibility for CAR T-cell therapies and lower cost, said Helen Heslop, MD, director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston. “In the longer term, there’re obviously a lot of people looking at how [the treatments] can be made more accessible. These are the first-generation CAR T [products], and I think there’ll be lots of refinements both to make them more effective and safer and also to use a third-party product to bring the cost of goods down.”

Other lingering unknowns about CAR T-cell therapies include how many patients in real-world clinical practice will have serious side effects, compared with those in trials, and the long-term recurrence rates after therapy use, Dr Gellad noted. He recently proposed in an article that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such therapies until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-4).

The current CAR T-cell therapies are only the beginning, said Dr Richard T Maziarz, MD, a bone marrow transplantation and blood cancer specialist at the Oregon Health and Science University Knight Cancer Institute in Portland. “Genetically engineered cell products are going to explode over the course of the next decade. This is not the end of the line, this is the starting point.”

Disclosures. Dr Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patents from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr Gellad reports grants from Express Scripts.

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, according to Carl June, MD, the Richard W Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia. That approval is anticipated sometime in 2019, and will “completely transform oncology,” Dr June said in a recent interview. “Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells.”

Researcher-turned-patient

The first treated patient in a trial of a novel anti–B-cell maturation antigen (BCMA)–specific CAR T-cell therapy (CART-BCMA)¹ developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset. Earlier this year, Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas (UT) Southwestern Medical Center in Dallas, outed himself as that first patient when he announced that CART-BCMA saved his life.²

Dr Wright had been diagnosed with multiple myeloma about 12 years ago and had failed 11 previous chemotherapies before he was enrolled in the CART-BCMA trial. He remains cancer free more than 2 years after receiving CART-BCMA and he’s now conducting CAR T-cell–related research in his UT Southwestern laboratory to broaden the effectiveness of current CAR T-cell therapies. In particular, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, because most patients who fail CAR T-cell therapy are elderly and might have terminally short telomeres. ²

Pharma lines up the trials

An ongoing University of Pennsylvania trial led by Adam D Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the 2016 annual meeting of the American Society of Hematology (ASH).³ In addition, multiple companies are pursuing registration trials for CAR T-cell therapies in myeloma, Dr June said.

Among those companies are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. The product was granted breakthrough therapy designation by the US Food and Drug Administration in November 2017 and will thus receive expedited review by the agency. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial.⁴ Updated findings from that trial were presented at the 2017 ASH annual meeting and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.⁵

Janssen Biotech Inc and Legend Biotech USA Inc/ Legend Biotech Ireland Ltd have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr June said. The companies announced in late 2017 that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate, LCAR-B38M.⁶ It has been accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
 

Cost, financial toxicity, and a new therapeutic landscape

The rush for the approval of a CAR T-cell therapy for myeloma will lead to a welcome addition to the treatment armamentarium not just because of the clinical benefits, but because of the possibility of reducing disease-related costs (p. e177). Although myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr June noted, and since many patients live with their disease for a long time, that can mean substantial “financial toxicity” being associated with treatment for the disease. “So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added.

Dr June explained that tisagenlecleucel, the first CAR T-cell therapy to be approved (in August 2017; p. e126), was for pediatric acute lymphoblastic leukemia that had relapsed at least twice.⁷ “That’s only about 600 kids a year in the United States, so it’s an ultra-orphan market,” he said. However, with the subsequent October 2017 approval of axicabtagene ciloleucel for certain cases of large B-cell lymphoma⁸ and the anticipated myeloma approval, CAR T-cell therapy will move away from that orphan status.

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s, when many voiced concern about the new therapy because it was available at only 2 centers in the United states and required a high level of specialized skill. “But over the years, millions of transplants have been done [and] they’re done at many community centers. And it’s the same thing with CARs.” There are now 30 centers offering CAR T-cell therapy and people have to be trained. “It’s a new skill set, and it will take time,” he said.
 

Access to trials: balancing demand and availability

That delay can be particularly frustrating because there are many patients who might benefit “in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr June noted.

“There’s more demand than availability, and it’s going to take a while” for that to change, he said. The solution most likely will involve the complementary use of off-the-shelf CAR T cells in some patients to induce remission and perhaps provide a bridge to another definitive therapy, and ultrapersonalized CAR T-cell therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

CRISPR-Cas9 gene editing is also being considered as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute-funded NYCE study,⁹ Dr June said. “We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial.”

Disclosures. Dr June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, according to Carl June, MD, the Richard W Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia. That approval is anticipated sometime in 2019, and will “completely transform oncology,” Dr June said in a recent interview. “Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells.”

Researcher-turned-patient

The first treated patient in a trial of a novel anti–B-cell maturation antigen (BCMA)–specific CAR T-cell therapy (CART-BCMA)¹ developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset. Earlier this year, Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas (UT) Southwestern Medical Center in Dallas, outed himself as that first patient when he announced that CART-BCMA saved his life.²

Dr Wright had been diagnosed with multiple myeloma about 12 years ago and had failed 11 previous chemotherapies before he was enrolled in the CART-BCMA trial. He remains cancer free more than 2 years after receiving CART-BCMA and he’s now conducting CAR T-cell–related research in his UT Southwestern laboratory to broaden the effectiveness of current CAR T-cell therapies. In particular, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, because most patients who fail CAR T-cell therapy are elderly and might have terminally short telomeres. ²

Pharma lines up the trials

An ongoing University of Pennsylvania trial led by Adam D Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the 2016 annual meeting of the American Society of Hematology (ASH).³ In addition, multiple companies are pursuing registration trials for CAR T-cell therapies in myeloma, Dr June said.

Among those companies are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. The product was granted breakthrough therapy designation by the US Food and Drug Administration in November 2017 and will thus receive expedited review by the agency. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial.⁴ Updated findings from that trial were presented at the 2017 ASH annual meeting and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.⁵

Janssen Biotech Inc and Legend Biotech USA Inc/ Legend Biotech Ireland Ltd have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr June said. The companies announced in late 2017 that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate, LCAR-B38M.⁶ It has been accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
 

Cost, financial toxicity, and a new therapeutic landscape

The rush for the approval of a CAR T-cell therapy for myeloma will lead to a welcome addition to the treatment armamentarium not just because of the clinical benefits, but because of the possibility of reducing disease-related costs (p. e177). Although myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr June noted, and since many patients live with their disease for a long time, that can mean substantial “financial toxicity” being associated with treatment for the disease. “So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added.

Dr June explained that tisagenlecleucel, the first CAR T-cell therapy to be approved (in August 2017; p. e126), was for pediatric acute lymphoblastic leukemia that had relapsed at least twice.⁷ “That’s only about 600 kids a year in the United States, so it’s an ultra-orphan market,” he said. However, with the subsequent October 2017 approval of axicabtagene ciloleucel for certain cases of large B-cell lymphoma⁸ and the anticipated myeloma approval, CAR T-cell therapy will move away from that orphan status.

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s, when many voiced concern about the new therapy because it was available at only 2 centers in the United states and required a high level of specialized skill. “But over the years, millions of transplants have been done [and] they’re done at many community centers. And it’s the same thing with CARs.” There are now 30 centers offering CAR T-cell therapy and people have to be trained. “It’s a new skill set, and it will take time,” he said.
 

Access to trials: balancing demand and availability

That delay can be particularly frustrating because there are many patients who might benefit “in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr June noted.

“There’s more demand than availability, and it’s going to take a while” for that to change, he said. The solution most likely will involve the complementary use of off-the-shelf CAR T cells in some patients to induce remission and perhaps provide a bridge to another definitive therapy, and ultrapersonalized CAR T-cell therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

CRISPR-Cas9 gene editing is also being considered as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute-funded NYCE study,⁹ Dr June said. “We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial.”

Disclosures. Dr June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, according to Carl June, MD, the Richard W Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia. That approval is anticipated sometime in 2019, and will “completely transform oncology,” Dr June said in a recent interview. “Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells.”

Researcher-turned-patient

The first treated patient in a trial of a novel anti–B-cell maturation antigen (BCMA)–specific CAR T-cell therapy (CART-BCMA)¹ developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset. Earlier this year, Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas (UT) Southwestern Medical Center in Dallas, outed himself as that first patient when he announced that CART-BCMA saved his life.²

Dr Wright had been diagnosed with multiple myeloma about 12 years ago and had failed 11 previous chemotherapies before he was enrolled in the CART-BCMA trial. He remains cancer free more than 2 years after receiving CART-BCMA and he’s now conducting CAR T-cell–related research in his UT Southwestern laboratory to broaden the effectiveness of current CAR T-cell therapies. In particular, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, because most patients who fail CAR T-cell therapy are elderly and might have terminally short telomeres. ²

Pharma lines up the trials

An ongoing University of Pennsylvania trial led by Adam D Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the 2016 annual meeting of the American Society of Hematology (ASH).³ In addition, multiple companies are pursuing registration trials for CAR T-cell therapies in myeloma, Dr June said.

Among those companies are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. The product was granted breakthrough therapy designation by the US Food and Drug Administration in November 2017 and will thus receive expedited review by the agency. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial.⁴ Updated findings from that trial were presented at the 2017 ASH annual meeting and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.⁵

Janssen Biotech Inc and Legend Biotech USA Inc/ Legend Biotech Ireland Ltd have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr June said. The companies announced in late 2017 that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate, LCAR-B38M.⁶ It has been accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
 

Cost, financial toxicity, and a new therapeutic landscape

The rush for the approval of a CAR T-cell therapy for myeloma will lead to a welcome addition to the treatment armamentarium not just because of the clinical benefits, but because of the possibility of reducing disease-related costs (p. e177). Although myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr June noted, and since many patients live with their disease for a long time, that can mean substantial “financial toxicity” being associated with treatment for the disease. “So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added.

Dr June explained that tisagenlecleucel, the first CAR T-cell therapy to be approved (in August 2017; p. e126), was for pediatric acute lymphoblastic leukemia that had relapsed at least twice.⁷ “That’s only about 600 kids a year in the United States, so it’s an ultra-orphan market,” he said. However, with the subsequent October 2017 approval of axicabtagene ciloleucel for certain cases of large B-cell lymphoma⁸ and the anticipated myeloma approval, CAR T-cell therapy will move away from that orphan status.

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s, when many voiced concern about the new therapy because it was available at only 2 centers in the United states and required a high level of specialized skill. “But over the years, millions of transplants have been done [and] they’re done at many community centers. And it’s the same thing with CARs.” There are now 30 centers offering CAR T-cell therapy and people have to be trained. “It’s a new skill set, and it will take time,” he said.
 

Access to trials: balancing demand and availability

That delay can be particularly frustrating because there are many patients who might benefit “in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr June noted.

“There’s more demand than availability, and it’s going to take a while” for that to change, he said. The solution most likely will involve the complementary use of off-the-shelf CAR T cells in some patients to induce remission and perhaps provide a bridge to another definitive therapy, and ultrapersonalized CAR T-cell therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

CRISPR-Cas9 gene editing is also being considered as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute-funded NYCE study,⁹ Dr June said. “We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial.”

Disclosures. Dr June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

The landmark US Food and Drug Administration approvals last year of tisagenlecleucel and axicabtagene ciloluecel – the first two chimeric antigen receptor (CAR) T-cell therapies for cancer – signified a new era of therapeutic possibilities (p. e126). CAR T-cells are a type of adoptive cell therapy or immunotherapy in which a patient’s immune cells are genetically engineered to target a tumor-associated antigen (in the case of these first two approvals, that target is CD19). In August, tisagenlecleucel got the green light for the treatment of B-cell precursor acute lymphoblastic leukemia in patients up to age 25 years, and in the fall, axicabtagene ciloluecel was approved for the treatment of refractory, aggressive B-cell non-Hodgkin lymphoma. The earlier this year, the agency also approved tisagenlecleucel for adult patients with relapsed or refractory large B-cell lymphoma. As Carl June, MD, a pioneer in CAR T-cell research notes in an interview on page e175, the next approval likely will be for multiple myeloma.

But while the science and the potential of these therapies are exciting, the impact of their cost and toxicities on patients tempers some of the enthusiasm. The Centers of Medicare & Medicaid Services is working on a final rule on payment for the inpatient administration of the two therapies for fiscal year 2019 and is considering the creation of a new Medicare Severity-Diagnosis Related Group code for procedures involving the use of CAR T-cell therapies (p. e177). Walid F Gellad, MD, of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, has said that some estimates for the cost of these therapies as high as $1.5 million per patient, and there is particular concern for the older adults who make up the Medicare population. These high costs would affect access to the therapy for many patients, irrespective of age, but one encouraging development on this front would be the development of lower-priced, off-the-shelf, third-party products. Another unknown with CAR T-cell therapies is the extent of side effects in real-world patients compared with those in trials, and what the long-term posttherapy recurrence rates would be.

In addition to highlighting CAR T-cell therapies in this issue, on page e167, Jane de Lartigue takes a look at tumor heterogeneity and the challenges it presents in the ongoing quest for effective cancer treatments. Dr de Lartigue describes the two key models used to explain how tumors develop – the clonal evolution model and the cancer stem cell model. She argues that although evidence suggests the models are not mutually exclusive and contribute to heterogeneity differently in different tumor types, heterogeneity and evolution, fueled by genomic alterations, are “intricately intertwined” in the development of cancer.

With cancer therapies come side effects, psychosocial effects, and sometimes challenges with posttreatment mobility, activities of daily living, and even self-care. Three articles in this issue deal with those posttreatment issues. On page e130, Kundu and colleagues report on a prospective study in which they evaluated physical and psychosocial functioning after diagnosis of prostate cancer and the factors associated with treatment satisfaction after treatment. They found that despite declines in erectile function and sexual domains, treatment satisfaction was more closely related to emotional, psychosocial, and nonsexual effects, underscoring the importance of assessing health-related quality-of-life outcomes beyond physical functioning. Forrest and colleagues (p. e138) set out to report outcomes of patients who received radiation therapy while on an inpatient rehabilitation facility and found that comprehensive care that includes radiation and rehabilitation at the inpatient rehabilitation facility level benefits appropriately selected patients. And on page e145, Ibrahim and colleagues tracked the effectiveness of a 12-week exercise program on long-term levels of upper-limb pain in young survivors of breast cancer and found that although there was some transient improvement in shoulder pain, it did not translate in to long-term benefits.

Our usual line-up of Case Reports on clinical challenges in the practice setting includes the case of a child with carcinoma of the colon (p. e152); two separate reports on patients with therapy-related skin reactions, one with radiation dermatitis (p.e156), the other with a reaction to a checkpoint inhibitor (p. e159); and a patient with recurrence of a small gastric gastrointestinal stromal tumor with high mitotic index (p. e163).

The landmark US Food and Drug Administration approvals last year of tisagenlecleucel and axicabtagene ciloluecel – the first two chimeric antigen receptor (CAR) T-cell therapies for cancer – signified a new era of therapeutic possibilities (p. e126). CAR T-cells are a type of adoptive cell therapy or immunotherapy in which a patient’s immune cells are genetically engineered to target a tumor-associated antigen (in the case of these first two approvals, that target is CD19). In August, tisagenlecleucel got the green light for the treatment of B-cell precursor acute lymphoblastic leukemia in patients up to age 25 years, and in the fall, axicabtagene ciloluecel was approved for the treatment of refractory, aggressive B-cell non-Hodgkin lymphoma. The earlier this year, the agency also approved tisagenlecleucel for adult patients with relapsed or refractory large B-cell lymphoma. As Carl June, MD, a pioneer in CAR T-cell research notes in an interview on page e175, the next approval likely will be for multiple myeloma.

But while the science and the potential of these therapies are exciting, the impact of their cost and toxicities on patients tempers some of the enthusiasm. The Centers of Medicare & Medicaid Services is working on a final rule on payment for the inpatient administration of the two therapies for fiscal year 2019 and is considering the creation of a new Medicare Severity-Diagnosis Related Group code for procedures involving the use of CAR T-cell therapies (p. e177). Walid F Gellad, MD, of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, has said that some estimates for the cost of these therapies as high as $1.5 million per patient, and there is particular concern for the older adults who make up the Medicare population. These high costs would affect access to the therapy for many patients, irrespective of age, but one encouraging development on this front would be the development of lower-priced, off-the-shelf, third-party products. Another unknown with CAR T-cell therapies is the extent of side effects in real-world patients compared with those in trials, and what the long-term posttherapy recurrence rates would be.

In addition to highlighting CAR T-cell therapies in this issue, on page e167, Jane de Lartigue takes a look at tumor heterogeneity and the challenges it presents in the ongoing quest for effective cancer treatments. Dr de Lartigue describes the two key models used to explain how tumors develop – the clonal evolution model and the cancer stem cell model. She argues that although evidence suggests the models are not mutually exclusive and contribute to heterogeneity differently in different tumor types, heterogeneity and evolution, fueled by genomic alterations, are “intricately intertwined” in the development of cancer.

With cancer therapies come side effects, psychosocial effects, and sometimes challenges with posttreatment mobility, activities of daily living, and even self-care. Three articles in this issue deal with those posttreatment issues. On page e130, Kundu and colleagues report on a prospective study in which they evaluated physical and psychosocial functioning after diagnosis of prostate cancer and the factors associated with treatment satisfaction after treatment. They found that despite declines in erectile function and sexual domains, treatment satisfaction was more closely related to emotional, psychosocial, and nonsexual effects, underscoring the importance of assessing health-related quality-of-life outcomes beyond physical functioning. Forrest and colleagues (p. e138) set out to report outcomes of patients who received radiation therapy while on an inpatient rehabilitation facility and found that comprehensive care that includes radiation and rehabilitation at the inpatient rehabilitation facility level benefits appropriately selected patients. And on page e145, Ibrahim and colleagues tracked the effectiveness of a 12-week exercise program on long-term levels of upper-limb pain in young survivors of breast cancer and found that although there was some transient improvement in shoulder pain, it did not translate in to long-term benefits.

Our usual line-up of Case Reports on clinical challenges in the practice setting includes the case of a child with carcinoma of the colon (p. e152); two separate reports on patients with therapy-related skin reactions, one with radiation dermatitis (p.e156), the other with a reaction to a checkpoint inhibitor (p. e159); and a patient with recurrence of a small gastric gastrointestinal stromal tumor with high mitotic index (p. e163).

The landmark US Food and Drug Administration approvals last year of tisagenlecleucel and axicabtagene ciloluecel – the first two chimeric antigen receptor (CAR) T-cell therapies for cancer – signified a new era of therapeutic possibilities (p. e126). CAR T-cells are a type of adoptive cell therapy or immunotherapy in which a patient’s immune cells are genetically engineered to target a tumor-associated antigen (in the case of these first two approvals, that target is CD19). In August, tisagenlecleucel got the green light for the treatment of B-cell precursor acute lymphoblastic leukemia in patients up to age 25 years, and in the fall, axicabtagene ciloluecel was approved for the treatment of refractory, aggressive B-cell non-Hodgkin lymphoma. The earlier this year, the agency also approved tisagenlecleucel for adult patients with relapsed or refractory large B-cell lymphoma. As Carl June, MD, a pioneer in CAR T-cell research notes in an interview on page e175, the next approval likely will be for multiple myeloma.

But while the science and the potential of these therapies are exciting, the impact of their cost and toxicities on patients tempers some of the enthusiasm. The Centers of Medicare & Medicaid Services is working on a final rule on payment for the inpatient administration of the two therapies for fiscal year 2019 and is considering the creation of a new Medicare Severity-Diagnosis Related Group code for procedures involving the use of CAR T-cell therapies (p. e177). Walid F Gellad, MD, of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, has said that some estimates for the cost of these therapies as high as $1.5 million per patient, and there is particular concern for the older adults who make up the Medicare population. These high costs would affect access to the therapy for many patients, irrespective of age, but one encouraging development on this front would be the development of lower-priced, off-the-shelf, third-party products. Another unknown with CAR T-cell therapies is the extent of side effects in real-world patients compared with those in trials, and what the long-term posttherapy recurrence rates would be.

In addition to highlighting CAR T-cell therapies in this issue, on page e167, Jane de Lartigue takes a look at tumor heterogeneity and the challenges it presents in the ongoing quest for effective cancer treatments. Dr de Lartigue describes the two key models used to explain how tumors develop – the clonal evolution model and the cancer stem cell model. She argues that although evidence suggests the models are not mutually exclusive and contribute to heterogeneity differently in different tumor types, heterogeneity and evolution, fueled by genomic alterations, are “intricately intertwined” in the development of cancer.

With cancer therapies come side effects, psychosocial effects, and sometimes challenges with posttreatment mobility, activities of daily living, and even self-care. Three articles in this issue deal with those posttreatment issues. On page e130, Kundu and colleagues report on a prospective study in which they evaluated physical and psychosocial functioning after diagnosis of prostate cancer and the factors associated with treatment satisfaction after treatment. They found that despite declines in erectile function and sexual domains, treatment satisfaction was more closely related to emotional, psychosocial, and nonsexual effects, underscoring the importance of assessing health-related quality-of-life outcomes beyond physical functioning. Forrest and colleagues (p. e138) set out to report outcomes of patients who received radiation therapy while on an inpatient rehabilitation facility and found that comprehensive care that includes radiation and rehabilitation at the inpatient rehabilitation facility level benefits appropriately selected patients. And on page e145, Ibrahim and colleagues tracked the effectiveness of a 12-week exercise program on long-term levels of upper-limb pain in young survivors of breast cancer and found that although there was some transient improvement in shoulder pain, it did not translate in to long-term benefits.

Our usual line-up of Case Reports on clinical challenges in the practice setting includes the case of a child with carcinoma of the colon (p. e152); two separate reports on patients with therapy-related skin reactions, one with radiation dermatitis (p.e156), the other with a reaction to a checkpoint inhibitor (p. e159); and a patient with recurrence of a small gastric gastrointestinal stromal tumor with high mitotic index (p. e163).