DURBAN, SOUTH AFRICA – A novel single-tablet, triple-antiretroviral combination regimen outperformed the well-established combination of ritonavir-boosted atazanavir plus tenofovir/emtricitabine in the ARIA trial, a phase IIIb study conducted in treatment-naive women with HIV infection.

The fixed-dose once-daily combination of dolutegravir 50 mg/abacavir 600 mg/lamivudine 300 mg, marketed in the United States as Triumeq since its approval in 2014, showed superior efficacy and a more favorable safety profile than did ritonavir-boosted atazanavir (Reyataz) plus tenofovir/emtricitabine (Truvada), Catherine Orrell, MD, reported at the 21st International AIDS Conference.

ARIA was a 48-week open-label randomized trial involving 495 treatment-naive HIV-infected women in the United States and 11 other countries. The primary endpoint – a plasma HIV RNA viral load below 50 copies/mL after 48 weeks of treatment – was achieved in 82% of patients on dolutegravir/abacavir/lamivudine (DTG/ABC/3TC), compared with 71% on ritonavir-boosted atazanavir plus tenofovir/emtricitabine (ATV+RTV+FTC/TDF).

Of note, the difference in efficacy was even more pronounced among women with a baseline viral load in excess of 100,000 copies/mL: an 80% success rate in attaining a viral load of less than 50 copies/mL at 48 weeks in the DTG/ABC/3TC group, compared with 64% in the comparator arm. Women with this baseline massive viral load comprised 28% of study participants, added Dr. Orrell of the University of Cape Town, South Africa.

To be eligible for the study, women had to be negative for an HLA-B*5701 genetic screen for allergic hypersensitivity to abacavir.

A particularly attractive feature of DTG/ABC/3TC is that dolutegravir, an unboosted integrin strand transfer inhibitor, provides a high barrier to development of drug resistance. Indeed, no subjects in the dolutegravir arm developed treatment-emergent primary integrin strand transfer inhibitor or abacavir/lamivudine resistance mutations, according to Dr. Orrell.

The superior efficacy of the single-tablet regimen was driven in part by fewer discontinuations due to adverse events: a 4% rate versus 7% in the comparator arm. Another key factor was the substantially lower virologic failure rate in DTG/ABC/3TC-treated women: 6% versus 14% in the comparator arm.

The single-tablet regimen also had a better safety profile. The combined rate of the most common drug-related adverse events – nausea, diarrhea, headache, and jaundice – was 22% in the DTG/ABC/3TC group compared with 38% with ATV+RTV+FTC/TDF.

The incidence of treatment-emergent psychiatric events – insomnia, anxiety, depression, or suicidal ideation – was roughly 14% in each treatment arm. That’s an important finding because some other studies have found an increase in psychiatric events in patients receiving integrin strand transfer inhibitors.

“The overall results, I think, are important for the field,” Kimberly Smith, MD, said at a press conference highlighting the ARIA trial.

“Women are often underrepresented in HIV clinical trials even though they bear much of the burden of the HIV epidemic,” added Dr. Smith, vice president for global medical strategy and head of research and development at ViiV Healthcare in Research Triangle Park, N.C.

“This fixed-dose combination is a winner,” said Salim Abdool Karim, MD, director of the Center for the AIDS Program of Research in South Africa, Durban, who chaired the press conference.

Dr. Orrell received a research grant from ViiV Healthcare, which sponsored the ARIA study.

[email protected]

DURBAN, SOUTH AFRICA – A novel single-tablet, triple-antiretroviral combination regimen outperformed the well-established combination of ritonavir-boosted atazanavir plus tenofovir/emtricitabine in the ARIA trial, a phase IIIb study conducted in treatment-naive women with HIV infection.

The fixed-dose once-daily combination of dolutegravir 50 mg/abacavir 600 mg/lamivudine 300 mg, marketed in the United States as Triumeq since its approval in 2014, showed superior efficacy and a more favorable safety profile than did ritonavir-boosted atazanavir (Reyataz) plus tenofovir/emtricitabine (Truvada), Catherine Orrell, MD, reported at the 21st International AIDS Conference.

ARIA was a 48-week open-label randomized trial involving 495 treatment-naive HIV-infected women in the United States and 11 other countries. The primary endpoint – a plasma HIV RNA viral load below 50 copies/mL after 48 weeks of treatment – was achieved in 82% of patients on dolutegravir/abacavir/lamivudine (DTG/ABC/3TC), compared with 71% on ritonavir-boosted atazanavir plus tenofovir/emtricitabine (ATV+RTV+FTC/TDF).

Of note, the difference in efficacy was even more pronounced among women with a baseline viral load in excess of 100,000 copies/mL: an 80% success rate in attaining a viral load of less than 50 copies/mL at 48 weeks in the DTG/ABC/3TC group, compared with 64% in the comparator arm. Women with this baseline massive viral load comprised 28% of study participants, added Dr. Orrell of the University of Cape Town, South Africa.

To be eligible for the study, women had to be negative for an HLA-B*5701 genetic screen for allergic hypersensitivity to abacavir.

A particularly attractive feature of DTG/ABC/3TC is that dolutegravir, an unboosted integrin strand transfer inhibitor, provides a high barrier to development of drug resistance. Indeed, no subjects in the dolutegravir arm developed treatment-emergent primary integrin strand transfer inhibitor or abacavir/lamivudine resistance mutations, according to Dr. Orrell.

The superior efficacy of the single-tablet regimen was driven in part by fewer discontinuations due to adverse events: a 4% rate versus 7% in the comparator arm. Another key factor was the substantially lower virologic failure rate in DTG/ABC/3TC-treated women: 6% versus 14% in the comparator arm.

The single-tablet regimen also had a better safety profile. The combined rate of the most common drug-related adverse events – nausea, diarrhea, headache, and jaundice – was 22% in the DTG/ABC/3TC group compared with 38% with ATV+RTV+FTC/TDF.

The incidence of treatment-emergent psychiatric events – insomnia, anxiety, depression, or suicidal ideation – was roughly 14% in each treatment arm. That’s an important finding because some other studies have found an increase in psychiatric events in patients receiving integrin strand transfer inhibitors.

“The overall results, I think, are important for the field,” Kimberly Smith, MD, said at a press conference highlighting the ARIA trial.

“Women are often underrepresented in HIV clinical trials even though they bear much of the burden of the HIV epidemic,” added Dr. Smith, vice president for global medical strategy and head of research and development at ViiV Healthcare in Research Triangle Park, N.C.

“This fixed-dose combination is a winner,” said Salim Abdool Karim, MD, director of the Center for the AIDS Program of Research in South Africa, Durban, who chaired the press conference.

Dr. Orrell received a research grant from ViiV Healthcare, which sponsored the ARIA study.

[email protected]

DURBAN, SOUTH AFRICA – A novel single-tablet, triple-antiretroviral combination regimen outperformed the well-established combination of ritonavir-boosted atazanavir plus tenofovir/emtricitabine in the ARIA trial, a phase IIIb study conducted in treatment-naive women with HIV infection.

The fixed-dose once-daily combination of dolutegravir 50 mg/abacavir 600 mg/lamivudine 300 mg, marketed in the United States as Triumeq since its approval in 2014, showed superior efficacy and a more favorable safety profile than did ritonavir-boosted atazanavir (Reyataz) plus tenofovir/emtricitabine (Truvada), Catherine Orrell, MD, reported at the 21st International AIDS Conference.

ARIA was a 48-week open-label randomized trial involving 495 treatment-naive HIV-infected women in the United States and 11 other countries. The primary endpoint – a plasma HIV RNA viral load below 50 copies/mL after 48 weeks of treatment – was achieved in 82% of patients on dolutegravir/abacavir/lamivudine (DTG/ABC/3TC), compared with 71% on ritonavir-boosted atazanavir plus tenofovir/emtricitabine (ATV+RTV+FTC/TDF).

Of note, the difference in efficacy was even more pronounced among women with a baseline viral load in excess of 100,000 copies/mL: an 80% success rate in attaining a viral load of less than 50 copies/mL at 48 weeks in the DTG/ABC/3TC group, compared with 64% in the comparator arm. Women with this baseline massive viral load comprised 28% of study participants, added Dr. Orrell of the University of Cape Town, South Africa.

To be eligible for the study, women had to be negative for an HLA-B*5701 genetic screen for allergic hypersensitivity to abacavir.

A particularly attractive feature of DTG/ABC/3TC is that dolutegravir, an unboosted integrin strand transfer inhibitor, provides a high barrier to development of drug resistance. Indeed, no subjects in the dolutegravir arm developed treatment-emergent primary integrin strand transfer inhibitor or abacavir/lamivudine resistance mutations, according to Dr. Orrell.

The superior efficacy of the single-tablet regimen was driven in part by fewer discontinuations due to adverse events: a 4% rate versus 7% in the comparator arm. Another key factor was the substantially lower virologic failure rate in DTG/ABC/3TC-treated women: 6% versus 14% in the comparator arm.

The single-tablet regimen also had a better safety profile. The combined rate of the most common drug-related adverse events – nausea, diarrhea, headache, and jaundice – was 22% in the DTG/ABC/3TC group compared with 38% with ATV+RTV+FTC/TDF.

The incidence of treatment-emergent psychiatric events – insomnia, anxiety, depression, or suicidal ideation – was roughly 14% in each treatment arm. That’s an important finding because some other studies have found an increase in psychiatric events in patients receiving integrin strand transfer inhibitors.

“The overall results, I think, are important for the field,” Kimberly Smith, MD, said at a press conference highlighting the ARIA trial.

“Women are often underrepresented in HIV clinical trials even though they bear much of the burden of the HIV epidemic,” added Dr. Smith, vice president for global medical strategy and head of research and development at ViiV Healthcare in Research Triangle Park, N.C.

“This fixed-dose combination is a winner,” said Salim Abdool Karim, MD, director of the Center for the AIDS Program of Research in South Africa, Durban, who chaired the press conference.

Dr. Orrell received a research grant from ViiV Healthcare, which sponsored the ARIA study.

[email protected]

Rotavirus detection was found to be diminished after rotavirus vaccine licensure, which is consistent with herd immunity, according to Harvey W. Kaufman, MD, and Zhen Chen.

During the 11-year period, 276,949 specimens were submitted for rotavirus antigen detection. In the prevaccine period, the laboratory performed an average of 31,800 tests for rotavirus antigen detection annually, of which 21% were positive. During the postvaccine period, an average of 20,981 annual tests were performed, with only 6% having a positive result, which represents an 82% reduction in the total number of positive results and a 73% reduction in the positivity rate (P less than .001). In the transition period, the positivity rate for rotavirus antigen detection was 14%, which represents a 27% reduction in the positive number and a 32% reduction in the positivity rate, compared with the prevaccine period (P less than .001).

©jarun011/Thinkstock

The study noted that the positivity rate during each of the three periods was nearly identical for boys and girls, with 21.1% for boys and 20.9% for girls during the prevaccine period, 9.8% for boys and 9.6% for girls in the transition period, and 4.9% for boys and 4.6% for girls in the postvaccine period.

“The data support the notion of herd immunity in children unlikely to have been vaccinated,” the researchers concluded. “Although the postvaccination period featured alternating years of higher and lower positivity, the peak seasons have a lower positivity rate than in the prevaccination period.”

Find the full study in Pediatrics (2016 Sept. 23. doi: 10.1542/peds.2016-1173).

llaubach@frontlinemedcomom

Rotavirus detection was found to be diminished after rotavirus vaccine licensure, which is consistent with herd immunity, according to Harvey W. Kaufman, MD, and Zhen Chen.

During the 11-year period, 276,949 specimens were submitted for rotavirus antigen detection. In the prevaccine period, the laboratory performed an average of 31,800 tests for rotavirus antigen detection annually, of which 21% were positive. During the postvaccine period, an average of 20,981 annual tests were performed, with only 6% having a positive result, which represents an 82% reduction in the total number of positive results and a 73% reduction in the positivity rate (P less than .001). In the transition period, the positivity rate for rotavirus antigen detection was 14%, which represents a 27% reduction in the positive number and a 32% reduction in the positivity rate, compared with the prevaccine period (P less than .001).

©jarun011/Thinkstock

The study noted that the positivity rate during each of the three periods was nearly identical for boys and girls, with 21.1% for boys and 20.9% for girls during the prevaccine period, 9.8% for boys and 9.6% for girls in the transition period, and 4.9% for boys and 4.6% for girls in the postvaccine period.

“The data support the notion of herd immunity in children unlikely to have been vaccinated,” the researchers concluded. “Although the postvaccination period featured alternating years of higher and lower positivity, the peak seasons have a lower positivity rate than in the prevaccination period.”

Find the full study in Pediatrics (2016 Sept. 23. doi: 10.1542/peds.2016-1173).

llaubach@frontlinemedcomom

Rotavirus detection was found to be diminished after rotavirus vaccine licensure, which is consistent with herd immunity, according to Harvey W. Kaufman, MD, and Zhen Chen.

During the 11-year period, 276,949 specimens were submitted for rotavirus antigen detection. In the prevaccine period, the laboratory performed an average of 31,800 tests for rotavirus antigen detection annually, of which 21% were positive. During the postvaccine period, an average of 20,981 annual tests were performed, with only 6% having a positive result, which represents an 82% reduction in the total number of positive results and a 73% reduction in the positivity rate (P less than .001). In the transition period, the positivity rate for rotavirus antigen detection was 14%, which represents a 27% reduction in the positive number and a 32% reduction in the positivity rate, compared with the prevaccine period (P less than .001).

©jarun011/Thinkstock

The study noted that the positivity rate during each of the three periods was nearly identical for boys and girls, with 21.1% for boys and 20.9% for girls during the prevaccine period, 9.8% for boys and 9.6% for girls in the transition period, and 4.9% for boys and 4.6% for girls in the postvaccine period.

“The data support the notion of herd immunity in children unlikely to have been vaccinated,” the researchers concluded. “Although the postvaccination period featured alternating years of higher and lower positivity, the peak seasons have a lower positivity rate than in the prevaccination period.”

Find the full study in Pediatrics (2016 Sept. 23. doi: 10.1542/peds.2016-1173).

llaubach@frontlinemedcomom

Four of nine acute myeloid leukemia patients went into complete remission – and a fifth responded – after being transfused with donor natural killer cells in a phase I study from Washington University in St. Louis.

The natural killer (NK) cells had been differentiated into “memorylike” NK cells by brief exposure to interleukin (IL) 12, 15, and 18 prior to transfusion. Although NK cells have traditionally been considered part of the innate immune system, it’s become clear recently that they have some adaptive abilities. The cytokine exposure in the St. Louis study seemed, in a sense, to train NK cells to remember and attack acute myeloid leukemia (AML).

The treated cells had enhanced interferon gamma production and cytotoxicity against AML cells in vitro. Once in the patients, they “proliferated extensively” and demonstrated robust responses against leukemia targets. Preactivation of NK cells with IL-12, IL-15, and IL-18 promotes “potent antileukemia functionality in vitro and in vivo and thus represent[s] a promising immunotherapy strategy for AML,” said investigators led by Rizwan Romee, MD, of the oncology division and clinical director of the haploidentical transplant program at Washington University (Sci Transl Med. 2016 Sep. 21. doi: 10.1126/scitranslmed.aaf2341).

NK cell therapy is an emerging treatment for AML, but it’s been unclear, at least until now, how best to maximize the cells’ anti-AML effect before transfer.

Prior studies have tried IL-2 or IL-15 overnight, which does increase NK cell functional capacity, but the effect is rapidly lost after transfer into patients.

That didn’t seem to be much of a problem when NK cells were differentiated into memorylike cells. “The longer-lasting increase in functional capacity ... combined with improved AML recognition, [enhanced] in vivo expansion and antileukemia responses, result[ed] in a several week ‘window of opportunity’ to attack AML blasts.” the authors said.

For safety, the initial cell dose was a tenth or twentieth of the typical adoptive NK cell dose. Even so, the memorylike cells consistently expanded to become greater than 90% of blood and most of bone marrow NK cells, which was “remarkable,” they said.

The National Cancer Institute and others funded the work. The authors had no disclosures.

[email protected]

Four of nine acute myeloid leukemia patients went into complete remission – and a fifth responded – after being transfused with donor natural killer cells in a phase I study from Washington University in St. Louis.

The natural killer (NK) cells had been differentiated into “memorylike” NK cells by brief exposure to interleukin (IL) 12, 15, and 18 prior to transfusion. Although NK cells have traditionally been considered part of the innate immune system, it’s become clear recently that they have some adaptive abilities. The cytokine exposure in the St. Louis study seemed, in a sense, to train NK cells to remember and attack acute myeloid leukemia (AML).

The treated cells had enhanced interferon gamma production and cytotoxicity against AML cells in vitro. Once in the patients, they “proliferated extensively” and demonstrated robust responses against leukemia targets. Preactivation of NK cells with IL-12, IL-15, and IL-18 promotes “potent antileukemia functionality in vitro and in vivo and thus represent[s] a promising immunotherapy strategy for AML,” said investigators led by Rizwan Romee, MD, of the oncology division and clinical director of the haploidentical transplant program at Washington University (Sci Transl Med. 2016 Sep. 21. doi: 10.1126/scitranslmed.aaf2341).

NK cell therapy is an emerging treatment for AML, but it’s been unclear, at least until now, how best to maximize the cells’ anti-AML effect before transfer.

Prior studies have tried IL-2 or IL-15 overnight, which does increase NK cell functional capacity, but the effect is rapidly lost after transfer into patients.

That didn’t seem to be much of a problem when NK cells were differentiated into memorylike cells. “The longer-lasting increase in functional capacity ... combined with improved AML recognition, [enhanced] in vivo expansion and antileukemia responses, result[ed] in a several week ‘window of opportunity’ to attack AML blasts.” the authors said.

For safety, the initial cell dose was a tenth or twentieth of the typical adoptive NK cell dose. Even so, the memorylike cells consistently expanded to become greater than 90% of blood and most of bone marrow NK cells, which was “remarkable,” they said.

The National Cancer Institute and others funded the work. The authors had no disclosures.

[email protected]

Four of nine acute myeloid leukemia patients went into complete remission – and a fifth responded – after being transfused with donor natural killer cells in a phase I study from Washington University in St. Louis.

The natural killer (NK) cells had been differentiated into “memorylike” NK cells by brief exposure to interleukin (IL) 12, 15, and 18 prior to transfusion. Although NK cells have traditionally been considered part of the innate immune system, it’s become clear recently that they have some adaptive abilities. The cytokine exposure in the St. Louis study seemed, in a sense, to train NK cells to remember and attack acute myeloid leukemia (AML).

The treated cells had enhanced interferon gamma production and cytotoxicity against AML cells in vitro. Once in the patients, they “proliferated extensively” and demonstrated robust responses against leukemia targets. Preactivation of NK cells with IL-12, IL-15, and IL-18 promotes “potent antileukemia functionality in vitro and in vivo and thus represent[s] a promising immunotherapy strategy for AML,” said investigators led by Rizwan Romee, MD, of the oncology division and clinical director of the haploidentical transplant program at Washington University (Sci Transl Med. 2016 Sep. 21. doi: 10.1126/scitranslmed.aaf2341).

NK cell therapy is an emerging treatment for AML, but it’s been unclear, at least until now, how best to maximize the cells’ anti-AML effect before transfer.

Prior studies have tried IL-2 or IL-15 overnight, which does increase NK cell functional capacity, but the effect is rapidly lost after transfer into patients.

That didn’t seem to be much of a problem when NK cells were differentiated into memorylike cells. “The longer-lasting increase in functional capacity ... combined with improved AML recognition, [enhanced] in vivo expansion and antileukemia responses, result[ed] in a several week ‘window of opportunity’ to attack AML blasts.” the authors said.

For safety, the initial cell dose was a tenth or twentieth of the typical adoptive NK cell dose. Even so, the memorylike cells consistently expanded to become greater than 90% of blood and most of bone marrow NK cells, which was “remarkable,” they said.

The National Cancer Institute and others funded the work. The authors had no disclosures.

[email protected]

Hossein Khiabanian, PhD

Photo by Debbie Vogel

New research has revealed relapse-specific mutations in pediatric acute lymphoblastic leukemia (ALL) and suggests that mutations in the RAS family may drive both resistance and sensitivity to treatment.

Specifically, the study showed that KRAS-mutant ALL cells were resistant to methotrexate but exhibited increased sensitivity to vincristine.

Hossein Khiabanian, PhD, of Rutgers Cancer Institute of New Jersey, and his colleagues reported these findings in PNAS.

The researchers performed whole-exome and whole-genome sequencing on samples from 55 pediatric patients with relapsed ALL, identified specific genomic changes, and validated these findings in 279 additional samples.

“We found that ALL relapse emerges from small, often clinically undetectable populations of cancer cells that are only partially genetically similar to the dominant leukemic population at diagnosis,” Dr Khiabanian said. “We also identified numerous new mutations in genes involved in drug resistance that are specific to relapsed ALL.”

In the first 55 patients (33 T-cell ALLs and 22 B-cell precursor ALLs), the researchers identified 27 recurrently mutated genes whose mutations were preferentially selected or retained at the time of relapse.

The team said 23 (85%) of these mutated genes were not previously implicated in ALL relapse—HTR3A, MED12, USP9X, CACNA1H, TENM3, AACS, SAMD4A, ANO5, PAPPA, NAALADL2, HIST3H2A, FZD7, TBX15, NEB, GREB1L, PLXNA4, SGK223, TSC1, PTPRG, FGF10, SYCP2, TRPM3, and EYS.

The researchers found mutations in the same genes when they analyzed 49 paired diagnosis and relapse B-cell precursor ALL samples as well as an additional 230 relapsed B-cell precursor ALL samples. In addition, the analyses revealed mutations in NT5C2, NR3C1, CREBBP, KMT2D, JAK2, JAK3, and TP53.

The team also noted that some patient samples showed retention or emergence of RAS mutant clones at relapse. In other patients, RAS mutant clones that were present at diagnosis were replaced by RAS wild-type populations at relapse.

The researchers said this suggests a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia.

To investigate this further, they analyzed mouse and human wild-type and mutant RAS isogenic leukemia cells. In these experiments, KRAS-mutant cells showed increased sensitivity to vincristine and increased resistance to methotrexate.

“These results highlight how drug therapy can impact the evolution of leukemia and show a previously unrecognized role of RAS mutations as causes of both sensitivity and resistance to chemotherapy,” Dr Khiabanian said.

“Early identification of these mutations, as well as other genetic alterations that have been shown to induce therapeutic resistance in leukemia patients, is pertinent in guiding precision medicine treatment strategies and prevention of relapsed disease—a goal that is now being pursued in my lab at Rutgers.”

Hossein Khiabanian, PhD

Photo by Debbie Vogel

New research has revealed relapse-specific mutations in pediatric acute lymphoblastic leukemia (ALL) and suggests that mutations in the RAS family may drive both resistance and sensitivity to treatment.

Specifically, the study showed that KRAS-mutant ALL cells were resistant to methotrexate but exhibited increased sensitivity to vincristine.

Hossein Khiabanian, PhD, of Rutgers Cancer Institute of New Jersey, and his colleagues reported these findings in PNAS.

The researchers performed whole-exome and whole-genome sequencing on samples from 55 pediatric patients with relapsed ALL, identified specific genomic changes, and validated these findings in 279 additional samples.

“We found that ALL relapse emerges from small, often clinically undetectable populations of cancer cells that are only partially genetically similar to the dominant leukemic population at diagnosis,” Dr Khiabanian said. “We also identified numerous new mutations in genes involved in drug resistance that are specific to relapsed ALL.”

In the first 55 patients (33 T-cell ALLs and 22 B-cell precursor ALLs), the researchers identified 27 recurrently mutated genes whose mutations were preferentially selected or retained at the time of relapse.

The team said 23 (85%) of these mutated genes were not previously implicated in ALL relapse—HTR3A, MED12, USP9X, CACNA1H, TENM3, AACS, SAMD4A, ANO5, PAPPA, NAALADL2, HIST3H2A, FZD7, TBX15, NEB, GREB1L, PLXNA4, SGK223, TSC1, PTPRG, FGF10, SYCP2, TRPM3, and EYS.

The researchers found mutations in the same genes when they analyzed 49 paired diagnosis and relapse B-cell precursor ALL samples as well as an additional 230 relapsed B-cell precursor ALL samples. In addition, the analyses revealed mutations in NT5C2, NR3C1, CREBBP, KMT2D, JAK2, JAK3, and TP53.

The team also noted that some patient samples showed retention or emergence of RAS mutant clones at relapse. In other patients, RAS mutant clones that were present at diagnosis were replaced by RAS wild-type populations at relapse.

The researchers said this suggests a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia.

To investigate this further, they analyzed mouse and human wild-type and mutant RAS isogenic leukemia cells. In these experiments, KRAS-mutant cells showed increased sensitivity to vincristine and increased resistance to methotrexate.

“These results highlight how drug therapy can impact the evolution of leukemia and show a previously unrecognized role of RAS mutations as causes of both sensitivity and resistance to chemotherapy,” Dr Khiabanian said.

“Early identification of these mutations, as well as other genetic alterations that have been shown to induce therapeutic resistance in leukemia patients, is pertinent in guiding precision medicine treatment strategies and prevention of relapsed disease—a goal that is now being pursued in my lab at Rutgers.”

Hossein Khiabanian, PhD

Photo by Debbie Vogel

New research has revealed relapse-specific mutations in pediatric acute lymphoblastic leukemia (ALL) and suggests that mutations in the RAS family may drive both resistance and sensitivity to treatment.

Specifically, the study showed that KRAS-mutant ALL cells were resistant to methotrexate but exhibited increased sensitivity to vincristine.

Hossein Khiabanian, PhD, of Rutgers Cancer Institute of New Jersey, and his colleagues reported these findings in PNAS.

The researchers performed whole-exome and whole-genome sequencing on samples from 55 pediatric patients with relapsed ALL, identified specific genomic changes, and validated these findings in 279 additional samples.

“We found that ALL relapse emerges from small, often clinically undetectable populations of cancer cells that are only partially genetically similar to the dominant leukemic population at diagnosis,” Dr Khiabanian said. “We also identified numerous new mutations in genes involved in drug resistance that are specific to relapsed ALL.”

In the first 55 patients (33 T-cell ALLs and 22 B-cell precursor ALLs), the researchers identified 27 recurrently mutated genes whose mutations were preferentially selected or retained at the time of relapse.

The team said 23 (85%) of these mutated genes were not previously implicated in ALL relapse—HTR3A, MED12, USP9X, CACNA1H, TENM3, AACS, SAMD4A, ANO5, PAPPA, NAALADL2, HIST3H2A, FZD7, TBX15, NEB, GREB1L, PLXNA4, SGK223, TSC1, PTPRG, FGF10, SYCP2, TRPM3, and EYS.

The researchers found mutations in the same genes when they analyzed 49 paired diagnosis and relapse B-cell precursor ALL samples as well as an additional 230 relapsed B-cell precursor ALL samples. In addition, the analyses revealed mutations in NT5C2, NR3C1, CREBBP, KMT2D, JAK2, JAK3, and TP53.

The team also noted that some patient samples showed retention or emergence of RAS mutant clones at relapse. In other patients, RAS mutant clones that were present at diagnosis were replaced by RAS wild-type populations at relapse.

The researchers said this suggests a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia.

To investigate this further, they analyzed mouse and human wild-type and mutant RAS isogenic leukemia cells. In these experiments, KRAS-mutant cells showed increased sensitivity to vincristine and increased resistance to methotrexate.

“These results highlight how drug therapy can impact the evolution of leukemia and show a previously unrecognized role of RAS mutations as causes of both sensitivity and resistance to chemotherapy,” Dr Khiabanian said.

“Early identification of these mutations, as well as other genetic alterations that have been shown to induce therapeutic resistance in leukemia patients, is pertinent in guiding precision medicine treatment strategies and prevention of relapsed disease—a goal that is now being pursued in my lab at Rutgers.”

AML cells

Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).

The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.

“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.

Salzman and his colleagues detailed their work in the journal Neuron.

Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.

aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.

The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.

The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.

The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.

The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.

Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.

The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.

For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.

“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.

AML cells

Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).

The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.

“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.

Salzman and his colleagues detailed their work in the journal Neuron.

Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.

aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.

The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.

The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.

The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.

The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.

Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.

The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.

For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.

“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.

AML cells

Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).

The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.

“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.

Salzman and his colleagues detailed their work in the journal Neuron.

Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.

aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.

The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.

The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.

The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.

The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.

Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.

The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.

For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.

“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.

Plasmodium sporozoite

Image by Ute Frevert

and Margaret Shear

The US Food and Drug Administration (FDA) has granted fast track designation to an investigational malaria vaccine.

Sanaria® PfSPZ Vaccine is composed of live but weakened Plasmodium falciparum sporozoites and is being developed by Sanaria, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Trials of Sanaria® PfSPZ Vaccine

In a phase 1 study published in Science in 2013, 80% of patients who received higher doses of Sanaria® PfSPZ Vaccine were protected from malaria at 3 weeks after vaccination.

In another phase 1 study published in Nature Medicine in 2016, 4 doses of the vaccine protected 73% of subjects from malaria at 3 weeks and 55% of subjects at 21 weeks.

Five of the subjects without parasitemia at 21 weeks were exposed to malaria-carrying mosquitoes again at 59 weeks, and none developed parasitemia.

To date, 1165 volunteers have received Sanaria’s PfSPZ-based products in more than 2 dozen clinical trials in the US, Europe, and Africa.

Clinical trials are in progress in Tanzania, Kenya, Mali, Burkina Faso, Germany, and the US, and are intended to begin soon in Equatorial Guinea.

Plasmodium sporozoite

Image by Ute Frevert

and Margaret Shear

The US Food and Drug Administration (FDA) has granted fast track designation to an investigational malaria vaccine.

Sanaria® PfSPZ Vaccine is composed of live but weakened Plasmodium falciparum sporozoites and is being developed by Sanaria, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Trials of Sanaria® PfSPZ Vaccine

In a phase 1 study published in Science in 2013, 80% of patients who received higher doses of Sanaria® PfSPZ Vaccine were protected from malaria at 3 weeks after vaccination.

In another phase 1 study published in Nature Medicine in 2016, 4 doses of the vaccine protected 73% of subjects from malaria at 3 weeks and 55% of subjects at 21 weeks.

Five of the subjects without parasitemia at 21 weeks were exposed to malaria-carrying mosquitoes again at 59 weeks, and none developed parasitemia.

To date, 1165 volunteers have received Sanaria’s PfSPZ-based products in more than 2 dozen clinical trials in the US, Europe, and Africa.

Clinical trials are in progress in Tanzania, Kenya, Mali, Burkina Faso, Germany, and the US, and are intended to begin soon in Equatorial Guinea.

Plasmodium sporozoite

Image by Ute Frevert

and Margaret Shear

The US Food and Drug Administration (FDA) has granted fast track designation to an investigational malaria vaccine.

Sanaria® PfSPZ Vaccine is composed of live but weakened Plasmodium falciparum sporozoites and is being developed by Sanaria, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Trials of Sanaria® PfSPZ Vaccine

In a phase 1 study published in Science in 2013, 80% of patients who received higher doses of Sanaria® PfSPZ Vaccine were protected from malaria at 3 weeks after vaccination.

In another phase 1 study published in Nature Medicine in 2016, 4 doses of the vaccine protected 73% of subjects from malaria at 3 weeks and 55% of subjects at 21 weeks.

Five of the subjects without parasitemia at 21 weeks were exposed to malaria-carrying mosquitoes again at 59 weeks, and none developed parasitemia.

To date, 1165 volunteers have received Sanaria’s PfSPZ-based products in more than 2 dozen clinical trials in the US, Europe, and Africa.

Clinical trials are in progress in Tanzania, Kenya, Mali, Burkina Faso, Germany, and the US, and are intended to begin soon in Equatorial Guinea.

Layer of cells lining a blood

vessel with nuclei in blue,

protein skeletons in red,

and beta-catenin in green.

Image courtesy of

NYU Langone Medical Center

Drugs intended to treat high blood pressure might also be effective for treating cerebral malaria, according to preclinical research published in the Journal of Clinical Investigation.

Researchers tested these drugs—angiotensin II (Ang II) receptor modulators—in mice.

In an initial experiment, 2 of the drugs—losartan and CGP-42112A—reduced the incidence of cerebral malaria.

In another experiment, 2 other Ang II receptor modulators—irbesartan and compound 21 (C21)—were each combined with the antimalarial chloroquine.

Both combinations improved survival in mice with cerebral malaria when compared to chloroquine alone.

“About 1 in 5 patients with cerebral malaria die within 48 hours of being admitted to the hospital—the time it takes for the parasite-killing drug to take effect,” said study author Ana Rodriguez, PhD, of NYU Langone Medical Center in New York.

“If we could add a drug that stopped hemorrhages during that window, it would buy time and save lives.”

With this research, Dr Rodriguez and her colleagues showed that Ang II receptor modulators inhibit the activation of beta-catenin, a protein that plays a key role in cerebral malaria.

The team found that when Plasmodium falciparum–infected red blood cells rupture over human brain microvascular endothelial cells, this activates beta-catenin, which mediates the disruption of interendothelial junctions.

But inhibiting the activation of beta-catenin with Ang II receptor modulators protects endothelial cells from this disruption.

The researchers demonstrated this by infecting mice with P berghei ANKA, treating them with losartan or CGP-42112A, and monitoring them for neurological symptoms.

Seventy-five percent of control mice developed cerebral malaria, compared to 13.3% of mice treated with losartan and 28.5% treated with CGP-42112A.

In another experiment, the researchers treated malaria-infected mice with chloroquine, alone or in combination with irbesartan or C21, only after neurological signs were evident.

The team observed an increase in survival for mice treated with irbesartan or C21. The survival rate was 18% for the mice treated only with chloroquine, 65% for mice given irbesartan, and 73% percent for mice treated with C21.

The researchers also found that mice treated with irbesartan or C21 experienced fewer, smaller hemorrhages. And, in most cases, these mice fully recovered.

Dr Rodriguez and her colleagues said the next steps for this research will be to investigate the exact molecules coming from ruptured P falciparum–infected red blood cells that signal to beta-catenin in vessel walls, and to conduct trials that test the effects of Ang II receptor modulators in patients with cerebral malaria.

Layer of cells lining a blood

vessel with nuclei in blue,

protein skeletons in red,

and beta-catenin in green.

Image courtesy of

NYU Langone Medical Center

Drugs intended to treat high blood pressure might also be effective for treating cerebral malaria, according to preclinical research published in the Journal of Clinical Investigation.

Researchers tested these drugs—angiotensin II (Ang II) receptor modulators—in mice.

In an initial experiment, 2 of the drugs—losartan and CGP-42112A—reduced the incidence of cerebral malaria.

In another experiment, 2 other Ang II receptor modulators—irbesartan and compound 21 (C21)—were each combined with the antimalarial chloroquine.

Both combinations improved survival in mice with cerebral malaria when compared to chloroquine alone.

“About 1 in 5 patients with cerebral malaria die within 48 hours of being admitted to the hospital—the time it takes for the parasite-killing drug to take effect,” said study author Ana Rodriguez, PhD, of NYU Langone Medical Center in New York.

“If we could add a drug that stopped hemorrhages during that window, it would buy time and save lives.”

With this research, Dr Rodriguez and her colleagues showed that Ang II receptor modulators inhibit the activation of beta-catenin, a protein that plays a key role in cerebral malaria.

The team found that when Plasmodium falciparum–infected red blood cells rupture over human brain microvascular endothelial cells, this activates beta-catenin, which mediates the disruption of interendothelial junctions.

But inhibiting the activation of beta-catenin with Ang II receptor modulators protects endothelial cells from this disruption.

The researchers demonstrated this by infecting mice with P berghei ANKA, treating them with losartan or CGP-42112A, and monitoring them for neurological symptoms.

Seventy-five percent of control mice developed cerebral malaria, compared to 13.3% of mice treated with losartan and 28.5% treated with CGP-42112A.

In another experiment, the researchers treated malaria-infected mice with chloroquine, alone or in combination with irbesartan or C21, only after neurological signs were evident.

The team observed an increase in survival for mice treated with irbesartan or C21. The survival rate was 18% for the mice treated only with chloroquine, 65% for mice given irbesartan, and 73% percent for mice treated with C21.

The researchers also found that mice treated with irbesartan or C21 experienced fewer, smaller hemorrhages. And, in most cases, these mice fully recovered.

Dr Rodriguez and her colleagues said the next steps for this research will be to investigate the exact molecules coming from ruptured P falciparum–infected red blood cells that signal to beta-catenin in vessel walls, and to conduct trials that test the effects of Ang II receptor modulators in patients with cerebral malaria.

Layer of cells lining a blood

vessel with nuclei in blue,

protein skeletons in red,

and beta-catenin in green.

Image courtesy of

NYU Langone Medical Center

Drugs intended to treat high blood pressure might also be effective for treating cerebral malaria, according to preclinical research published in the Journal of Clinical Investigation.

Researchers tested these drugs—angiotensin II (Ang II) receptor modulators—in mice.

In an initial experiment, 2 of the drugs—losartan and CGP-42112A—reduced the incidence of cerebral malaria.

In another experiment, 2 other Ang II receptor modulators—irbesartan and compound 21 (C21)—were each combined with the antimalarial chloroquine.

Both combinations improved survival in mice with cerebral malaria when compared to chloroquine alone.

“About 1 in 5 patients with cerebral malaria die within 48 hours of being admitted to the hospital—the time it takes for the parasite-killing drug to take effect,” said study author Ana Rodriguez, PhD, of NYU Langone Medical Center in New York.

“If we could add a drug that stopped hemorrhages during that window, it would buy time and save lives.”

With this research, Dr Rodriguez and her colleagues showed that Ang II receptor modulators inhibit the activation of beta-catenin, a protein that plays a key role in cerebral malaria.

The team found that when Plasmodium falciparum–infected red blood cells rupture over human brain microvascular endothelial cells, this activates beta-catenin, which mediates the disruption of interendothelial junctions.

But inhibiting the activation of beta-catenin with Ang II receptor modulators protects endothelial cells from this disruption.

The researchers demonstrated this by infecting mice with P berghei ANKA, treating them with losartan or CGP-42112A, and monitoring them for neurological symptoms.

Seventy-five percent of control mice developed cerebral malaria, compared to 13.3% of mice treated with losartan and 28.5% treated with CGP-42112A.

In another experiment, the researchers treated malaria-infected mice with chloroquine, alone or in combination with irbesartan or C21, only after neurological signs were evident.

The team observed an increase in survival for mice treated with irbesartan or C21. The survival rate was 18% for the mice treated only with chloroquine, 65% for mice given irbesartan, and 73% percent for mice treated with C21.

The researchers also found that mice treated with irbesartan or C21 experienced fewer, smaller hemorrhages. And, in most cases, these mice fully recovered.

Dr Rodriguez and her colleagues said the next steps for this research will be to investigate the exact molecules coming from ruptured P falciparum–infected red blood cells that signal to beta-catenin in vessel walls, and to conduct trials that test the effects of Ang II receptor modulators in patients with cerebral malaria.

COLUMBUS, OHIO – The disparity in amputation rates between blacks and non-Hispanic whites in Chicago was higher than the national average and up to five times greater on the predominantly black South Side than on the predominantly white North Side of the city.

The reasons for this disparity are unclear, but a recent study of white and black Chicagoans has shown that the rates at which the races self-report claudication do not differ, suggesting that better utilization of public health resources in the black community could potentially reduce this disparity.

Reporting at the annual meeting of the Midwestern Vascular Surgery Society, lead investigator Samantha Minc, MD, of Rush University in Chicago, said the difference in amputation rates may be traced to later recognition of disease in nonwhites.

“Possible reasons for late recognition of disease include lack of access to care, communication issues with doctors, education issues, or the patient and/or caregiver and primary care provider having difficulty accessing specialists,” Dr. Minc said. “Another often-cited explanation for the late recognition is the possibility of differences in disease symptom manifestations in nonwhites, which is what we chose to study.”

Investigators from Rush University analyzed data from a combined cohort of Chicago residents age 65 years and older from two studies of aging: The Rush Memory and Aging Project and the Minority Aging Research Study.

Because of the segregated nature of Chicago – the North Side is mostly white, the South Side mostly black and the West Side mostly Hispanic – prior research has coupled census data with the Illinois Department of Public Health database to analyze care patterns. This data showed that the disparity in amputation rates among groups in Chicago was higher than the national average and up to five times greater on the South Side, compared with the North, Dr. Minc said.

The latest study matched blacks and whites from both studies 1:2 based on age, education, gender, and length of follow-up. In all, a cohort of 2,487 subjects was generated: 801 blacks and 1,686 non-Hispanic whites. Among blacks, 6.5% reported claudication at baseline, compared with 5.9% of whites, and at any point of the study 19.5% of blacks and 19.6% of non-Hispanic whites reported claudication, differences that were not statistically significant.

Blacks did have higher rates of diabetes, 27% vs. 12.6%, were more likely to have used tobacco, more likely to be female, and were slightly younger on average, but other demographic factors – such as income or rates of congestive heart failure and coronary artery disease – were not significantly different, Dr. Minc said.

The study findings will inform the Chicago Department of Public Health’s Healthy Chicago 2.0 initiative to reduce the disparity in amputation rates between whites and blacks by 10% by 2020.

Dr. Minc acknowledged limitations of the study, among them that participants were volunteers, aged 65 years and older, and 72% female, that Hispanics were excluded, and that the use of the Modified Rose/World Health Organization questionnaire to detect claudication is “specific, but not very sensitive.”

“Our findings suggest that the delay in recognition in disease in nonwhites is not due to a racial differences in disease manifestation or symptomatology and that addressing socioeconomic issues, such as access to care, communication, and education may reduce the racial disparity in amputation rates,” Dr. Minc said. “Public health resources should focus on early recognition of the disease in higher-risk groups to decrease this disparity.”

Dr. Minc and her coauthors had no relationships to disclose.

COLUMBUS, OHIO – The disparity in amputation rates between blacks and non-Hispanic whites in Chicago was higher than the national average and up to five times greater on the predominantly black South Side than on the predominantly white North Side of the city.

The reasons for this disparity are unclear, but a recent study of white and black Chicagoans has shown that the rates at which the races self-report claudication do not differ, suggesting that better utilization of public health resources in the black community could potentially reduce this disparity.

Reporting at the annual meeting of the Midwestern Vascular Surgery Society, lead investigator Samantha Minc, MD, of Rush University in Chicago, said the difference in amputation rates may be traced to later recognition of disease in nonwhites.

“Possible reasons for late recognition of disease include lack of access to care, communication issues with doctors, education issues, or the patient and/or caregiver and primary care provider having difficulty accessing specialists,” Dr. Minc said. “Another often-cited explanation for the late recognition is the possibility of differences in disease symptom manifestations in nonwhites, which is what we chose to study.”

Investigators from Rush University analyzed data from a combined cohort of Chicago residents age 65 years and older from two studies of aging: The Rush Memory and Aging Project and the Minority Aging Research Study.

Because of the segregated nature of Chicago – the North Side is mostly white, the South Side mostly black and the West Side mostly Hispanic – prior research has coupled census data with the Illinois Department of Public Health database to analyze care patterns. This data showed that the disparity in amputation rates among groups in Chicago was higher than the national average and up to five times greater on the South Side, compared with the North, Dr. Minc said.

The latest study matched blacks and whites from both studies 1:2 based on age, education, gender, and length of follow-up. In all, a cohort of 2,487 subjects was generated: 801 blacks and 1,686 non-Hispanic whites. Among blacks, 6.5% reported claudication at baseline, compared with 5.9% of whites, and at any point of the study 19.5% of blacks and 19.6% of non-Hispanic whites reported claudication, differences that were not statistically significant.

Blacks did have higher rates of diabetes, 27% vs. 12.6%, were more likely to have used tobacco, more likely to be female, and were slightly younger on average, but other demographic factors – such as income or rates of congestive heart failure and coronary artery disease – were not significantly different, Dr. Minc said.

The study findings will inform the Chicago Department of Public Health’s Healthy Chicago 2.0 initiative to reduce the disparity in amputation rates between whites and blacks by 10% by 2020.

Dr. Minc acknowledged limitations of the study, among them that participants were volunteers, aged 65 years and older, and 72% female, that Hispanics were excluded, and that the use of the Modified Rose/World Health Organization questionnaire to detect claudication is “specific, but not very sensitive.”

“Our findings suggest that the delay in recognition in disease in nonwhites is not due to a racial differences in disease manifestation or symptomatology and that addressing socioeconomic issues, such as access to care, communication, and education may reduce the racial disparity in amputation rates,” Dr. Minc said. “Public health resources should focus on early recognition of the disease in higher-risk groups to decrease this disparity.”

Dr. Minc and her coauthors had no relationships to disclose.

COLUMBUS, OHIO – The disparity in amputation rates between blacks and non-Hispanic whites in Chicago was higher than the national average and up to five times greater on the predominantly black South Side than on the predominantly white North Side of the city.

The reasons for this disparity are unclear, but a recent study of white and black Chicagoans has shown that the rates at which the races self-report claudication do not differ, suggesting that better utilization of public health resources in the black community could potentially reduce this disparity.

Reporting at the annual meeting of the Midwestern Vascular Surgery Society, lead investigator Samantha Minc, MD, of Rush University in Chicago, said the difference in amputation rates may be traced to later recognition of disease in nonwhites.

“Possible reasons for late recognition of disease include lack of access to care, communication issues with doctors, education issues, or the patient and/or caregiver and primary care provider having difficulty accessing specialists,” Dr. Minc said. “Another often-cited explanation for the late recognition is the possibility of differences in disease symptom manifestations in nonwhites, which is what we chose to study.”

Investigators from Rush University analyzed data from a combined cohort of Chicago residents age 65 years and older from two studies of aging: The Rush Memory and Aging Project and the Minority Aging Research Study.

Because of the segregated nature of Chicago – the North Side is mostly white, the South Side mostly black and the West Side mostly Hispanic – prior research has coupled census data with the Illinois Department of Public Health database to analyze care patterns. This data showed that the disparity in amputation rates among groups in Chicago was higher than the national average and up to five times greater on the South Side, compared with the North, Dr. Minc said.

The latest study matched blacks and whites from both studies 1:2 based on age, education, gender, and length of follow-up. In all, a cohort of 2,487 subjects was generated: 801 blacks and 1,686 non-Hispanic whites. Among blacks, 6.5% reported claudication at baseline, compared with 5.9% of whites, and at any point of the study 19.5% of blacks and 19.6% of non-Hispanic whites reported claudication, differences that were not statistically significant.

Blacks did have higher rates of diabetes, 27% vs. 12.6%, were more likely to have used tobacco, more likely to be female, and were slightly younger on average, but other demographic factors – such as income or rates of congestive heart failure and coronary artery disease – were not significantly different, Dr. Minc said.

The study findings will inform the Chicago Department of Public Health’s Healthy Chicago 2.0 initiative to reduce the disparity in amputation rates between whites and blacks by 10% by 2020.

Dr. Minc acknowledged limitations of the study, among them that participants were volunteers, aged 65 years and older, and 72% female, that Hispanics were excluded, and that the use of the Modified Rose/World Health Organization questionnaire to detect claudication is “specific, but not very sensitive.”

“Our findings suggest that the delay in recognition in disease in nonwhites is not due to a racial differences in disease manifestation or symptomatology and that addressing socioeconomic issues, such as access to care, communication, and education may reduce the racial disparity in amputation rates,” Dr. Minc said. “Public health resources should focus on early recognition of the disease in higher-risk groups to decrease this disparity.”

Dr. Minc and her coauthors had no relationships to disclose.

The Food and Drug Administration approved an extended-release combination of canagliflozin and metformin for first-line use as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes, according to Janssen Pharmaceuticals.

Once-daily Invokamet XR combines canagliflozin (Invokana) and an extended-release formulation of metformin. Studies in healthy adults have shown that Invokamet XR results in the same levels of canagliflozin and metformin in the body as when corresponding dosages of the two medicines are administered as separate tablets.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

Phase III studies showed that using canagliflozin and metformin lowered blood sugar and, in prespecified secondary endpoints, was linked to greater reductions in body weight and systolic blood pressure.

Invokamet XR is available with 50 mg or 150 mg of canagliflozin, and 500 mg or 1,000 mg of extended-release metformin. Invokamet XR contains a boxed warning regarding the risk of lactic acidosis.

Read the full company statement here.

[email protected]

The Food and Drug Administration approved an extended-release combination of canagliflozin and metformin for first-line use as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes, according to Janssen Pharmaceuticals.

Once-daily Invokamet XR combines canagliflozin (Invokana) and an extended-release formulation of metformin. Studies in healthy adults have shown that Invokamet XR results in the same levels of canagliflozin and metformin in the body as when corresponding dosages of the two medicines are administered as separate tablets.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

Phase III studies showed that using canagliflozin and metformin lowered blood sugar and, in prespecified secondary endpoints, was linked to greater reductions in body weight and systolic blood pressure.

Invokamet XR is available with 50 mg or 150 mg of canagliflozin, and 500 mg or 1,000 mg of extended-release metformin. Invokamet XR contains a boxed warning regarding the risk of lactic acidosis.

Read the full company statement here.

[email protected]

The Food and Drug Administration approved an extended-release combination of canagliflozin and metformin for first-line use as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes, according to Janssen Pharmaceuticals.

Once-daily Invokamet XR combines canagliflozin (Invokana) and an extended-release formulation of metformin. Studies in healthy adults have shown that Invokamet XR results in the same levels of canagliflozin and metformin in the body as when corresponding dosages of the two medicines are administered as separate tablets.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

Phase III studies showed that using canagliflozin and metformin lowered blood sugar and, in prespecified secondary endpoints, was linked to greater reductions in body weight and systolic blood pressure.

Invokamet XR is available with 50 mg or 150 mg of canagliflozin, and 500 mg or 1,000 mg of extended-release metformin. Invokamet XR contains a boxed warning regarding the risk of lactic acidosis.

Read the full company statement here.

[email protected]

LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.

Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.

“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.

Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.

Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.

Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.

Versus interferon beta-1a

The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.

In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.

Versus fingolimod

The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.

“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.

Versus natalizumab

The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.

Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.

A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.

Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.

Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.

LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.

Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.

“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.

Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.

Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.

Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.

Versus interferon beta-1a

The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.

In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.

Versus fingolimod

The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.

“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.

Versus natalizumab

The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.

Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.

A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.

Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.

Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.

LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.

Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.

“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.

Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.

Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.

Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.

Versus interferon beta-1a

The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.

In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.

Versus fingolimod

The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.

“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.

Versus natalizumab

The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.

Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.

A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.

Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.

Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.