It might only take 1 month of antibiotics, not 9, to prevent tuberculosis in people with HIV, according to National Institute of Allergy and Infectious Diseases (NIAID) researchers.

A phase 3 trial, ACTG 5279, enrolled 3,000 people aged ≥ 13 years living with HIV. All participants lived in an area with a high tuberculosis (TB) burden or had a skin or blood test indicating latent infection. Among people with latent TB infection, HIV infection is the greatest risk factor for progression to active TB disease. About half were taking antiretroviral therapy (ART). The participants were randomly assigned to a 1-month course of rifapentine and isoniazid or 9 months of isoniazid. They were monitored for an average of 3 years.

Tuberculosis incidence was lower than expected and similar in both treatment groups: 32 participants in the 1-month group and 33 in the 9-month group developed active TB. Regardless of treatment, TB rates were higher among participants who were not taking ART when the study began, and among those with positive TB tests.

Adherence was high in both groups, but it was significantly better in the group with the shorter regimen. Nearly all (97%) of those in the 1-month group finished the full antibiotic course, compared with 90% in the 9-month group.

Few adverse events were reported in the 1-month group.

Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, and Robert Eisinger, PhD, special assistant for scientific projects at NIAID, have called for systems biology approaches using large datasets and modeling to understand how Mycobacterium tuberculosis infection causes disease. Noting that lengthy and complex treatment regimens make the disease increasingly difficult to cure, they say the ultimate treatment goal should be drug combinations administered for shorter time periods, as well as, a safe and more broadly effective vaccine and rapid, inexpensive diagnostic tests for drug-resistant TB.

It might only take 1 month of antibiotics, not 9, to prevent tuberculosis in people with HIV, according to National Institute of Allergy and Infectious Diseases (NIAID) researchers.

A phase 3 trial, ACTG 5279, enrolled 3,000 people aged ≥ 13 years living with HIV. All participants lived in an area with a high tuberculosis (TB) burden or had a skin or blood test indicating latent infection. Among people with latent TB infection, HIV infection is the greatest risk factor for progression to active TB disease. About half were taking antiretroviral therapy (ART). The participants were randomly assigned to a 1-month course of rifapentine and isoniazid or 9 months of isoniazid. They were monitored for an average of 3 years.

Tuberculosis incidence was lower than expected and similar in both treatment groups: 32 participants in the 1-month group and 33 in the 9-month group developed active TB. Regardless of treatment, TB rates were higher among participants who were not taking ART when the study began, and among those with positive TB tests.

Adherence was high in both groups, but it was significantly better in the group with the shorter regimen. Nearly all (97%) of those in the 1-month group finished the full antibiotic course, compared with 90% in the 9-month group.

Few adverse events were reported in the 1-month group.

Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, and Robert Eisinger, PhD, special assistant for scientific projects at NIAID, have called for systems biology approaches using large datasets and modeling to understand how Mycobacterium tuberculosis infection causes disease. Noting that lengthy and complex treatment regimens make the disease increasingly difficult to cure, they say the ultimate treatment goal should be drug combinations administered for shorter time periods, as well as, a safe and more broadly effective vaccine and rapid, inexpensive diagnostic tests for drug-resistant TB.

It might only take 1 month of antibiotics, not 9, to prevent tuberculosis in people with HIV, according to National Institute of Allergy and Infectious Diseases (NIAID) researchers.

A phase 3 trial, ACTG 5279, enrolled 3,000 people aged ≥ 13 years living with HIV. All participants lived in an area with a high tuberculosis (TB) burden or had a skin or blood test indicating latent infection. Among people with latent TB infection, HIV infection is the greatest risk factor for progression to active TB disease. About half were taking antiretroviral therapy (ART). The participants were randomly assigned to a 1-month course of rifapentine and isoniazid or 9 months of isoniazid. They were monitored for an average of 3 years.

Tuberculosis incidence was lower than expected and similar in both treatment groups: 32 participants in the 1-month group and 33 in the 9-month group developed active TB. Regardless of treatment, TB rates were higher among participants who were not taking ART when the study began, and among those with positive TB tests.

Adherence was high in both groups, but it was significantly better in the group with the shorter regimen. Nearly all (97%) of those in the 1-month group finished the full antibiotic course, compared with 90% in the 9-month group.

Few adverse events were reported in the 1-month group.

Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, and Robert Eisinger, PhD, special assistant for scientific projects at NIAID, have called for systems biology approaches using large datasets and modeling to understand how Mycobacterium tuberculosis infection causes disease. Noting that lengthy and complex treatment regimens make the disease increasingly difficult to cure, they say the ultimate treatment goal should be drug combinations administered for shorter time periods, as well as, a safe and more broadly effective vaccine and rapid, inexpensive diagnostic tests for drug-resistant TB.

Starting antiretroviral therapy (ART) right after diagnosis does not prevent the depletion of CD4+ T cells from the gut or help restore them—and researchers at the National Institutes of Health (NIH) may have found the reason. For the first time, the NIH says, scientists have shown a relationship between high levels of a “gut-homing” protein called α4β7 and HIV health outcomes.

The researchers found that women who had more CD4+ T cells with high levels of α4β7 were more likely to become infected with HIV, and the virus damaged their immune systems more rapidly than it did in women with fewer such cells.

Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID) and coauthor of the study paper found that HIV “preferentially infects” those cells. That leads to more HIV-infected CD4+ T cells moving to the gut, which in turn leads to extensive damage to gut-based immune cells.

In the study, which compared blood samples from 59 women shortly before they acquired HIV to those of 106 women who remained HIV negative, the risk of HIV acquisition rose by 18% for each 1% increase in α4β7 protein.

The α4β7 cells also “strongly affected” how quickly HIV damaged the immune system. CD4+ T-cell levels dropped twice as fast among women with higher pre-infection levels of α4β7. Within a few months, those women also had more HIV in the blood. The researchers say the mechanism for immune system damage was likely HIV-related damage to the gut, because higher pre-infection levels of α4β7 were associated with higher levels of a biologic marker of gut damage.

The study findings suggest that ART alone may not be enough; people with HIV may also benefit from interventions to restore CD4+ T cells in their gastrointestinal tracts. One possible solution could be vedolizumab, an anti- α4β7 antibody approved for treatment of ulcerative colitis and Crohn disease. In animal studies, vedolizumab contributed to “near replenishment” of CD4+ T cells.

To determine whether short-term treatment with vedolizumab in combination with ART could generate sustained HIV remission, NIAID has initiated an early-phase clinical trial.

Source:
US Department of Health and Human Services. National Institutes of Health. https://www.nih.gov/news-events/news-releases/study-links-gut-homing-protein-levels-hiv-infection-risk-disease-progression. Published January 24, 2018. Accessed April 19, 2018.

Starting antiretroviral therapy (ART) right after diagnosis does not prevent the depletion of CD4+ T cells from the gut or help restore them—and researchers at the National Institutes of Health (NIH) may have found the reason. For the first time, the NIH says, scientists have shown a relationship between high levels of a “gut-homing” protein called α4β7 and HIV health outcomes.

The researchers found that women who had more CD4+ T cells with high levels of α4β7 were more likely to become infected with HIV, and the virus damaged their immune systems more rapidly than it did in women with fewer such cells.

Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID) and coauthor of the study paper found that HIV “preferentially infects” those cells. That leads to more HIV-infected CD4+ T cells moving to the gut, which in turn leads to extensive damage to gut-based immune cells.

In the study, which compared blood samples from 59 women shortly before they acquired HIV to those of 106 women who remained HIV negative, the risk of HIV acquisition rose by 18% for each 1% increase in α4β7 protein.

The α4β7 cells also “strongly affected” how quickly HIV damaged the immune system. CD4+ T-cell levels dropped twice as fast among women with higher pre-infection levels of α4β7. Within a few months, those women also had more HIV in the blood. The researchers say the mechanism for immune system damage was likely HIV-related damage to the gut, because higher pre-infection levels of α4β7 were associated with higher levels of a biologic marker of gut damage.

The study findings suggest that ART alone may not be enough; people with HIV may also benefit from interventions to restore CD4+ T cells in their gastrointestinal tracts. One possible solution could be vedolizumab, an anti- α4β7 antibody approved for treatment of ulcerative colitis and Crohn disease. In animal studies, vedolizumab contributed to “near replenishment” of CD4+ T cells.

To determine whether short-term treatment with vedolizumab in combination with ART could generate sustained HIV remission, NIAID has initiated an early-phase clinical trial.

Source:
US Department of Health and Human Services. National Institutes of Health. https://www.nih.gov/news-events/news-releases/study-links-gut-homing-protein-levels-hiv-infection-risk-disease-progression. Published January 24, 2018. Accessed April 19, 2018.

Starting antiretroviral therapy (ART) right after diagnosis does not prevent the depletion of CD4+ T cells from the gut or help restore them—and researchers at the National Institutes of Health (NIH) may have found the reason. For the first time, the NIH says, scientists have shown a relationship between high levels of a “gut-homing” protein called α4β7 and HIV health outcomes.

The researchers found that women who had more CD4+ T cells with high levels of α4β7 were more likely to become infected with HIV, and the virus damaged their immune systems more rapidly than it did in women with fewer such cells.

Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID) and coauthor of the study paper found that HIV “preferentially infects” those cells. That leads to more HIV-infected CD4+ T cells moving to the gut, which in turn leads to extensive damage to gut-based immune cells.

In the study, which compared blood samples from 59 women shortly before they acquired HIV to those of 106 women who remained HIV negative, the risk of HIV acquisition rose by 18% for each 1% increase in α4β7 protein.

The α4β7 cells also “strongly affected” how quickly HIV damaged the immune system. CD4+ T-cell levels dropped twice as fast among women with higher pre-infection levels of α4β7. Within a few months, those women also had more HIV in the blood. The researchers say the mechanism for immune system damage was likely HIV-related damage to the gut, because higher pre-infection levels of α4β7 were associated with higher levels of a biologic marker of gut damage.

The study findings suggest that ART alone may not be enough; people with HIV may also benefit from interventions to restore CD4+ T cells in their gastrointestinal tracts. One possible solution could be vedolizumab, an anti- α4β7 antibody approved for treatment of ulcerative colitis and Crohn disease. In animal studies, vedolizumab contributed to “near replenishment” of CD4+ T cells.

To determine whether short-term treatment with vedolizumab in combination with ART could generate sustained HIV remission, NIAID has initiated an early-phase clinical trial.

Source:
US Department of Health and Human Services. National Institutes of Health. https://www.nih.gov/news-events/news-releases/study-links-gut-homing-protein-levels-hiv-infection-risk-disease-progression. Published January 24, 2018. Accessed April 19, 2018.

Research Hospital/Seth Dixon

Germline variants in IKZF1 can predispose carriers to acute lymphoblastic leukemia (ALL), according to a study published in Cancer Cell.

The research began with the discovery of an IKZF1 variant in 3 generations of a German family affected by pediatric ALL.

Researchers then analyzed data from nearly 5000 children with ALL and identified 27 additional germline variants in IKZF1.

These variants were present in 0.9% of the patients analyzed, and most of the patients with the variants had B-cell ALL.

“This finding adds to the growing body of evidence that, while germline variations still account for a small percentage of pediatric ALL cases overall, more children than previously recognized inherit a predisposition to develop ALL,” said Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

In the Cancer Cell paper, Dr Mullighan and his colleagues report the discovery of a germline deletion variant in IKZF1 (c.del556 or D186fs), which was present in 3 generations of a family.

Two of the 6 family members with this variant had developed B-ALL as children and died. The remaining 4 subjects are apparently healthy, despite having reduced numbers of B cells.

To build upon this discovery, the researchers performed targeted sequencing of IKZF1 in 4963 children with ALL.

This revealed 27 additional IKZF1 variants in 43 patients, most of whom had B-ALL. (One patient had T-cell ALL, and, for 8 patients, their subtype was unknown.)

The researchers noted that the variants were distributed across the gene.

“The pattern of IKZF1 variants was surprising because many of the variants were in regions of the gene that are rarely mutated in leukemic cells,” said study author Jun J. Yang, PhD, of St. Jude. “These regions of the gene have not been well characterized.”

The researchers also found that 22 of the 28 IKZF1 variants adversely affect gene function, while the remaining 6 variants appear to be benign.

The team said the deleterious variants impair DNA binding and regulation of transcriptional targets, induce aberrant leukemic cell adhesion, and reduce ALL cells’ sensitivity to treatment with dasatinib and dexamethasone.

The researchers identified the most deleterious variants as 5 that are located outside of the zinc-finger domains (M31V, M347V, R423C, A434G, and L449F), 2 variants affecting the N-terminal DNA-binding domain (R162P and H163Y), 2 truncating nonsense variants (M306* and C394*), and the frameshift variant discovered in the German family (D186fs).

“This [research] will expand the number of genes to consider when screening for predisposition to leukemia, particularly B-ALL,” said study author Kim Nichols, of St. Jude.

“And while not everyone carrying a germline IKZF1 variant will develop leukemia, these results will help us educate families about the potential risk of leukemia.”

Research Hospital/Seth Dixon

Germline variants in IKZF1 can predispose carriers to acute lymphoblastic leukemia (ALL), according to a study published in Cancer Cell.

The research began with the discovery of an IKZF1 variant in 3 generations of a German family affected by pediatric ALL.

Researchers then analyzed data from nearly 5000 children with ALL and identified 27 additional germline variants in IKZF1.

These variants were present in 0.9% of the patients analyzed, and most of the patients with the variants had B-cell ALL.

“This finding adds to the growing body of evidence that, while germline variations still account for a small percentage of pediatric ALL cases overall, more children than previously recognized inherit a predisposition to develop ALL,” said Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

In the Cancer Cell paper, Dr Mullighan and his colleagues report the discovery of a germline deletion variant in IKZF1 (c.del556 or D186fs), which was present in 3 generations of a family.

Two of the 6 family members with this variant had developed B-ALL as children and died. The remaining 4 subjects are apparently healthy, despite having reduced numbers of B cells.

To build upon this discovery, the researchers performed targeted sequencing of IKZF1 in 4963 children with ALL.

This revealed 27 additional IKZF1 variants in 43 patients, most of whom had B-ALL. (One patient had T-cell ALL, and, for 8 patients, their subtype was unknown.)

The researchers noted that the variants were distributed across the gene.

“The pattern of IKZF1 variants was surprising because many of the variants were in regions of the gene that are rarely mutated in leukemic cells,” said study author Jun J. Yang, PhD, of St. Jude. “These regions of the gene have not been well characterized.”

The researchers also found that 22 of the 28 IKZF1 variants adversely affect gene function, while the remaining 6 variants appear to be benign.

The team said the deleterious variants impair DNA binding and regulation of transcriptional targets, induce aberrant leukemic cell adhesion, and reduce ALL cells’ sensitivity to treatment with dasatinib and dexamethasone.

The researchers identified the most deleterious variants as 5 that are located outside of the zinc-finger domains (M31V, M347V, R423C, A434G, and L449F), 2 variants affecting the N-terminal DNA-binding domain (R162P and H163Y), 2 truncating nonsense variants (M306* and C394*), and the frameshift variant discovered in the German family (D186fs).

“This [research] will expand the number of genes to consider when screening for predisposition to leukemia, particularly B-ALL,” said study author Kim Nichols, of St. Jude.

“And while not everyone carrying a germline IKZF1 variant will develop leukemia, these results will help us educate families about the potential risk of leukemia.”

Research Hospital/Seth Dixon

Germline variants in IKZF1 can predispose carriers to acute lymphoblastic leukemia (ALL), according to a study published in Cancer Cell.

The research began with the discovery of an IKZF1 variant in 3 generations of a German family affected by pediatric ALL.

Researchers then analyzed data from nearly 5000 children with ALL and identified 27 additional germline variants in IKZF1.

These variants were present in 0.9% of the patients analyzed, and most of the patients with the variants had B-cell ALL.

“This finding adds to the growing body of evidence that, while germline variations still account for a small percentage of pediatric ALL cases overall, more children than previously recognized inherit a predisposition to develop ALL,” said Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

In the Cancer Cell paper, Dr Mullighan and his colleagues report the discovery of a germline deletion variant in IKZF1 (c.del556 or D186fs), which was present in 3 generations of a family.

Two of the 6 family members with this variant had developed B-ALL as children and died. The remaining 4 subjects are apparently healthy, despite having reduced numbers of B cells.

To build upon this discovery, the researchers performed targeted sequencing of IKZF1 in 4963 children with ALL.

This revealed 27 additional IKZF1 variants in 43 patients, most of whom had B-ALL. (One patient had T-cell ALL, and, for 8 patients, their subtype was unknown.)

The researchers noted that the variants were distributed across the gene.

“The pattern of IKZF1 variants was surprising because many of the variants were in regions of the gene that are rarely mutated in leukemic cells,” said study author Jun J. Yang, PhD, of St. Jude. “These regions of the gene have not been well characterized.”

The researchers also found that 22 of the 28 IKZF1 variants adversely affect gene function, while the remaining 6 variants appear to be benign.

The team said the deleterious variants impair DNA binding and regulation of transcriptional targets, induce aberrant leukemic cell adhesion, and reduce ALL cells’ sensitivity to treatment with dasatinib and dexamethasone.

The researchers identified the most deleterious variants as 5 that are located outside of the zinc-finger domains (M31V, M347V, R423C, A434G, and L449F), 2 variants affecting the N-terminal DNA-binding domain (R162P and H163Y), 2 truncating nonsense variants (M306* and C394*), and the frameshift variant discovered in the German family (D186fs).

“This [research] will expand the number of genes to consider when screening for predisposition to leukemia, particularly B-ALL,” said study author Kim Nichols, of St. Jude.

“And while not everyone carrying a germline IKZF1 variant will develop leukemia, these results will help us educate families about the potential risk of leukemia.”

Photo by Rhoda Baer

CHICAGO—Preclinical research suggests the pan-FLT3/pan-BTK inhibitor CG’806 is more effective than other kinase inhibitors in fighting certain hematologic malignancies.

In one study, CG’806 proved more potent than comparator drugs in primary samples of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL).

In another study, CG’806 demonstrated greater cytotoxicity than comparators in a range of malignant B cell lines.

Data from both studies were presented at the AACR Annual Meeting 2018 (abstracts 791 and 794).

The research was supported by Aptose Biosciences, Inc., the company developing CG’806.

CG’806 is a small molecule that inhibits wild-type (WT) FLT3, as well as FLT3 housing the ITD mutation or with point mutations in the tyrosine kinase domain (TKD, including D835G, D835Y, D835H) or in the gatekeeper region (F691L). CG’806 also inhibits BTK-WT and BTK-C481S.

Abstract 791

Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented results with CG’806 in primary patient samples.

The team found that CG’806 demonstrated greater potency against AML samples relative to other FLT3 inhibitors.

Median IC₅₀ values in 188 AML patient samples were 0.0765 µM for CG’806, 0.125 µM for gilteritinib, 0.199 µM for quizartinib, 0.551 µM for dovitinib, 2.25 µM for midostaurin, 2.93 µM for sorafenib, and 5.01 µM for crenolanib.

The researchers said CG’806 sensitivity was enhanced in FLT3-ITD and FLT3-TKD positive cases.

In CLL patient samples, CG’806 exhibited greater potency and a greater range of activity than the BTK inhibitor ibrutinib. Across 95 CLL samples, the median IC₅₀ values were 0.114 µM for CG’806 and 4.09 µM for ibrutinib.

The researchers said this greater potency of CG’806 may be due to the activity of CG’806 on CSF1R, which has been identified as a therapeutic target in CLL.

“The clinical benefit of current FLT3 inhibitors in AML is transient, as resistance develops after several months of treatment,” Dr Kurtz noted. “Similarly, ibrutinib . . . is limited by acquired resistance as well as refractory disease and tolerance challenges. As a pan-FLT3/pan-BTK inhibitor . . ., CG’806 offers important potential to address these limitations.”

Abstract 794

Hongying Zhang, MD, PhD, of Aptose Biosciences, and her colleagues presented results with CG’806 in malignant B-cell and AML cell lines.

The researchers found that CG’806 inhibited FLT3-ITD signaling and induced apoptosis more effectively than quizartinib in FLT3-ITD AML cells (MV4-11). The team noted that CG’806 caused G0/G1 cell-cycle arrest in the cells.

CG’806 also exhibited greater cytotoxic activity than quizartinib in FLT3-WT AML cell lines (KG-1 and NOMO-1).

In addition, CG’806 was more potent than quizartinib, gilteritinib, and crenolanib in Ba/F3 cells transfected with FLT3-WT, ITD, D835Y, and ITD-F691. CG’806 was more potent than quizartinib and crenolanib—but not gilteritinib—in Ba/F3 cells transfected with FLT3-ITD-D835Y.

The researchers said they found that CG’806 inhibits BTK, AURK, and downstream signals in FLT3-WT AML cells.

The team also found that CG’806 decreased BTK phosphorylation in all tested cell lines of B-cell malignancies. This included acute lymphoblastic leukemia, mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma cell lines.

Across all cell lines, CG’806 killed malignant B cells more effectively than ibrutinib. And CG’806 was “equally potent” against WT and C481S-mutant BTK, according to the researchers.

The team also said CG’806 inhibited AURK and induced polyploidy in B-cell malignancies.

“[C]G’806 has demonstrated the ability to kill a broad range of AML and B-cell malignancies through inhibition of multiple oncogenic pathways,” said William G. Rice, PhD, chairman and chief executive officer of Aptose.

“These studies are critical for understanding how to develop and position CG’806 as we prepare for clinical development in these challenging hematologic malignancies.”

Photo by Rhoda Baer

CHICAGO—Preclinical research suggests the pan-FLT3/pan-BTK inhibitor CG’806 is more effective than other kinase inhibitors in fighting certain hematologic malignancies.

In one study, CG’806 proved more potent than comparator drugs in primary samples of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL).

In another study, CG’806 demonstrated greater cytotoxicity than comparators in a range of malignant B cell lines.

Data from both studies were presented at the AACR Annual Meeting 2018 (abstracts 791 and 794).

The research was supported by Aptose Biosciences, Inc., the company developing CG’806.

CG’806 is a small molecule that inhibits wild-type (WT) FLT3, as well as FLT3 housing the ITD mutation or with point mutations in the tyrosine kinase domain (TKD, including D835G, D835Y, D835H) or in the gatekeeper region (F691L). CG’806 also inhibits BTK-WT and BTK-C481S.

Abstract 791

Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented results with CG’806 in primary patient samples.

The team found that CG’806 demonstrated greater potency against AML samples relative to other FLT3 inhibitors.

Median IC₅₀ values in 188 AML patient samples were 0.0765 µM for CG’806, 0.125 µM for gilteritinib, 0.199 µM for quizartinib, 0.551 µM for dovitinib, 2.25 µM for midostaurin, 2.93 µM for sorafenib, and 5.01 µM for crenolanib.

The researchers said CG’806 sensitivity was enhanced in FLT3-ITD and FLT3-TKD positive cases.

In CLL patient samples, CG’806 exhibited greater potency and a greater range of activity than the BTK inhibitor ibrutinib. Across 95 CLL samples, the median IC₅₀ values were 0.114 µM for CG’806 and 4.09 µM for ibrutinib.

The researchers said this greater potency of CG’806 may be due to the activity of CG’806 on CSF1R, which has been identified as a therapeutic target in CLL.

“The clinical benefit of current FLT3 inhibitors in AML is transient, as resistance develops after several months of treatment,” Dr Kurtz noted. “Similarly, ibrutinib . . . is limited by acquired resistance as well as refractory disease and tolerance challenges. As a pan-FLT3/pan-BTK inhibitor . . ., CG’806 offers important potential to address these limitations.”

Abstract 794

Hongying Zhang, MD, PhD, of Aptose Biosciences, and her colleagues presented results with CG’806 in malignant B-cell and AML cell lines.

The researchers found that CG’806 inhibited FLT3-ITD signaling and induced apoptosis more effectively than quizartinib in FLT3-ITD AML cells (MV4-11). The team noted that CG’806 caused G0/G1 cell-cycle arrest in the cells.

CG’806 also exhibited greater cytotoxic activity than quizartinib in FLT3-WT AML cell lines (KG-1 and NOMO-1).

In addition, CG’806 was more potent than quizartinib, gilteritinib, and crenolanib in Ba/F3 cells transfected with FLT3-WT, ITD, D835Y, and ITD-F691. CG’806 was more potent than quizartinib and crenolanib—but not gilteritinib—in Ba/F3 cells transfected with FLT3-ITD-D835Y.

The researchers said they found that CG’806 inhibits BTK, AURK, and downstream signals in FLT3-WT AML cells.

The team also found that CG’806 decreased BTK phosphorylation in all tested cell lines of B-cell malignancies. This included acute lymphoblastic leukemia, mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma cell lines.

Across all cell lines, CG’806 killed malignant B cells more effectively than ibrutinib. And CG’806 was “equally potent” against WT and C481S-mutant BTK, according to the researchers.

The team also said CG’806 inhibited AURK and induced polyploidy in B-cell malignancies.

“[C]G’806 has demonstrated the ability to kill a broad range of AML and B-cell malignancies through inhibition of multiple oncogenic pathways,” said William G. Rice, PhD, chairman and chief executive officer of Aptose.

“These studies are critical for understanding how to develop and position CG’806 as we prepare for clinical development in these challenging hematologic malignancies.”

Photo by Rhoda Baer

CHICAGO—Preclinical research suggests the pan-FLT3/pan-BTK inhibitor CG’806 is more effective than other kinase inhibitors in fighting certain hematologic malignancies.

In one study, CG’806 proved more potent than comparator drugs in primary samples of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL).

In another study, CG’806 demonstrated greater cytotoxicity than comparators in a range of malignant B cell lines.

Data from both studies were presented at the AACR Annual Meeting 2018 (abstracts 791 and 794).

The research was supported by Aptose Biosciences, Inc., the company developing CG’806.

CG’806 is a small molecule that inhibits wild-type (WT) FLT3, as well as FLT3 housing the ITD mutation or with point mutations in the tyrosine kinase domain (TKD, including D835G, D835Y, D835H) or in the gatekeeper region (F691L). CG’806 also inhibits BTK-WT and BTK-C481S.

Abstract 791

Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented results with CG’806 in primary patient samples.

The team found that CG’806 demonstrated greater potency against AML samples relative to other FLT3 inhibitors.

Median IC₅₀ values in 188 AML patient samples were 0.0765 µM for CG’806, 0.125 µM for gilteritinib, 0.199 µM for quizartinib, 0.551 µM for dovitinib, 2.25 µM for midostaurin, 2.93 µM for sorafenib, and 5.01 µM for crenolanib.

The researchers said CG’806 sensitivity was enhanced in FLT3-ITD and FLT3-TKD positive cases.

In CLL patient samples, CG’806 exhibited greater potency and a greater range of activity than the BTK inhibitor ibrutinib. Across 95 CLL samples, the median IC₅₀ values were 0.114 µM for CG’806 and 4.09 µM for ibrutinib.

The researchers said this greater potency of CG’806 may be due to the activity of CG’806 on CSF1R, which has been identified as a therapeutic target in CLL.

“The clinical benefit of current FLT3 inhibitors in AML is transient, as resistance develops after several months of treatment,” Dr Kurtz noted. “Similarly, ibrutinib . . . is limited by acquired resistance as well as refractory disease and tolerance challenges. As a pan-FLT3/pan-BTK inhibitor . . ., CG’806 offers important potential to address these limitations.”

Abstract 794

Hongying Zhang, MD, PhD, of Aptose Biosciences, and her colleagues presented results with CG’806 in malignant B-cell and AML cell lines.

The researchers found that CG’806 inhibited FLT3-ITD signaling and induced apoptosis more effectively than quizartinib in FLT3-ITD AML cells (MV4-11). The team noted that CG’806 caused G0/G1 cell-cycle arrest in the cells.

CG’806 also exhibited greater cytotoxic activity than quizartinib in FLT3-WT AML cell lines (KG-1 and NOMO-1).

In addition, CG’806 was more potent than quizartinib, gilteritinib, and crenolanib in Ba/F3 cells transfected with FLT3-WT, ITD, D835Y, and ITD-F691. CG’806 was more potent than quizartinib and crenolanib—but not gilteritinib—in Ba/F3 cells transfected with FLT3-ITD-D835Y.

The researchers said they found that CG’806 inhibits BTK, AURK, and downstream signals in FLT3-WT AML cells.

The team also found that CG’806 decreased BTK phosphorylation in all tested cell lines of B-cell malignancies. This included acute lymphoblastic leukemia, mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma cell lines.

Across all cell lines, CG’806 killed malignant B cells more effectively than ibrutinib. And CG’806 was “equally potent” against WT and C481S-mutant BTK, according to the researchers.

The team also said CG’806 inhibited AURK and induced polyploidy in B-cell malignancies.

“[C]G’806 has demonstrated the ability to kill a broad range of AML and B-cell malignancies through inhibition of multiple oncogenic pathways,” said William G. Rice, PhD, chairman and chief executive officer of Aptose.

“These studies are critical for understanding how to develop and position CG’806 as we prepare for clinical development in these challenging hematologic malignancies.”

Image by James Thomson

CHICAGO—Researchers have used induced pluripotent stem cells (iPSCs) to create a “universal” chimeric antigen receptor (CAR) T-cell therapy known as FT819.

The team says FT819 has the potential to be mass-produced, stored, and made readily available for cancer patients.

In in vitro experiments, FT819 demonstrated activity against leukemia and lymphoma.

These results were presented at the AACR Annual Meeting 2018 (abstract LB-108).

The research was conducted by employees of Fate Therapeutics, Inc., the company developing FT819, as well as Memorial Sloan-Kettering Cancer Center.

About FT819

FT819 is produced from a master iPSC line generated using T cells from healthy donors.

“A master iPSC line has unlimited capacity to self-renew and can be banked and renewably used,” said Bob Valamehr, PhD, vice-president of cancer immunotherapy at Fate Therapeutics, Inc.

“We started with cells from a healthy donor rather than the patient, created a master cell line, and used the master cell line to produce large quantities of ‘universal’ CAR19 T cells that are not patient-restricted. These first-of-kind CAR19 T cells, called FT819, can be packaged, stored, and made readily available for treatment of a large number of patients.”

FT819 has 2 targeting receptors—a CAR targeting CD19-positive tumor cells and a CD16 Fc receptor that can engage other therapies (such as tumor antigen-targeting monoclonal antibodies) to overcome antigen escape.

The master iPSC line used for the production of FT819 is engineered in a one-time event to insert a CD19 CAR into the T-cell receptor α constant (TRAC) locus. This is done to eliminate T-cell receptor expression and reduce the likelihood of graft-versus-host disease.

Previous research showed that targeting a CAR to the TRAC locus results in uniform CAR expression and enhances T-cell potency. In fact, TRAC-CAR T cells outperformed conventionally generated CAR T cells by preventing T-cell exhaustion in a mouse model of acute lymphoblastic leukemia.

In vitro experiments

With the current work, the researchers found that FT819 displayed an efficient cytotoxic T-cell response when challenged with CD19-positive tumor cells. FT819 produced cytokines (IFN-gamma, TNF-alpha, and IL-2) and mediators of cell death (CD107a/b, perforin, and granzyme B).

FT819 was also target-specific, attacking only CD19-positive tumor cells and sparing CD19-negative tumor cells in experiments with Raji (Burkitt lymphoma) and Nalm-6 (B-cell acute lymphoblastic leukemia) cell lines.

The researchers said they observed consistent antigen-specific cytotoxicity against Nalm-6 cells with FT819 but variability in antigen-specific cytotoxicity with conventional CAR T cells.

In addition, when combined with rituximab, FT819 elicited antibody-dependent cell-mediated cytotoxicity against CD19-negative, CD20-positive tumor cells.

“Through the development of FT819, we believe there is significant opportunity to lower the cost of CAR T-cell manufacture, enhance the quality of the product, and create a readily available supply of a more efficacious product to reach more patients in need,” Dr Valamehr said.

Image by James Thomson

CHICAGO—Researchers have used induced pluripotent stem cells (iPSCs) to create a “universal” chimeric antigen receptor (CAR) T-cell therapy known as FT819.

The team says FT819 has the potential to be mass-produced, stored, and made readily available for cancer patients.

In in vitro experiments, FT819 demonstrated activity against leukemia and lymphoma.

These results were presented at the AACR Annual Meeting 2018 (abstract LB-108).

The research was conducted by employees of Fate Therapeutics, Inc., the company developing FT819, as well as Memorial Sloan-Kettering Cancer Center.

About FT819

FT819 is produced from a master iPSC line generated using T cells from healthy donors.

“A master iPSC line has unlimited capacity to self-renew and can be banked and renewably used,” said Bob Valamehr, PhD, vice-president of cancer immunotherapy at Fate Therapeutics, Inc.

“We started with cells from a healthy donor rather than the patient, created a master cell line, and used the master cell line to produce large quantities of ‘universal’ CAR19 T cells that are not patient-restricted. These first-of-kind CAR19 T cells, called FT819, can be packaged, stored, and made readily available for treatment of a large number of patients.”

FT819 has 2 targeting receptors—a CAR targeting CD19-positive tumor cells and a CD16 Fc receptor that can engage other therapies (such as tumor antigen-targeting monoclonal antibodies) to overcome antigen escape.

The master iPSC line used for the production of FT819 is engineered in a one-time event to insert a CD19 CAR into the T-cell receptor α constant (TRAC) locus. This is done to eliminate T-cell receptor expression and reduce the likelihood of graft-versus-host disease.

Previous research showed that targeting a CAR to the TRAC locus results in uniform CAR expression and enhances T-cell potency. In fact, TRAC-CAR T cells outperformed conventionally generated CAR T cells by preventing T-cell exhaustion in a mouse model of acute lymphoblastic leukemia.

In vitro experiments

With the current work, the researchers found that FT819 displayed an efficient cytotoxic T-cell response when challenged with CD19-positive tumor cells. FT819 produced cytokines (IFN-gamma, TNF-alpha, and IL-2) and mediators of cell death (CD107a/b, perforin, and granzyme B).

FT819 was also target-specific, attacking only CD19-positive tumor cells and sparing CD19-negative tumor cells in experiments with Raji (Burkitt lymphoma) and Nalm-6 (B-cell acute lymphoblastic leukemia) cell lines.

The researchers said they observed consistent antigen-specific cytotoxicity against Nalm-6 cells with FT819 but variability in antigen-specific cytotoxicity with conventional CAR T cells.

In addition, when combined with rituximab, FT819 elicited antibody-dependent cell-mediated cytotoxicity against CD19-negative, CD20-positive tumor cells.

“Through the development of FT819, we believe there is significant opportunity to lower the cost of CAR T-cell manufacture, enhance the quality of the product, and create a readily available supply of a more efficacious product to reach more patients in need,” Dr Valamehr said.

Image by James Thomson

CHICAGO—Researchers have used induced pluripotent stem cells (iPSCs) to create a “universal” chimeric antigen receptor (CAR) T-cell therapy known as FT819.

The team says FT819 has the potential to be mass-produced, stored, and made readily available for cancer patients.

In in vitro experiments, FT819 demonstrated activity against leukemia and lymphoma.

These results were presented at the AACR Annual Meeting 2018 (abstract LB-108).

The research was conducted by employees of Fate Therapeutics, Inc., the company developing FT819, as well as Memorial Sloan-Kettering Cancer Center.

About FT819

FT819 is produced from a master iPSC line generated using T cells from healthy donors.

“A master iPSC line has unlimited capacity to self-renew and can be banked and renewably used,” said Bob Valamehr, PhD, vice-president of cancer immunotherapy at Fate Therapeutics, Inc.

“We started with cells from a healthy donor rather than the patient, created a master cell line, and used the master cell line to produce large quantities of ‘universal’ CAR19 T cells that are not patient-restricted. These first-of-kind CAR19 T cells, called FT819, can be packaged, stored, and made readily available for treatment of a large number of patients.”

FT819 has 2 targeting receptors—a CAR targeting CD19-positive tumor cells and a CD16 Fc receptor that can engage other therapies (such as tumor antigen-targeting monoclonal antibodies) to overcome antigen escape.

The master iPSC line used for the production of FT819 is engineered in a one-time event to insert a CD19 CAR into the T-cell receptor α constant (TRAC) locus. This is done to eliminate T-cell receptor expression and reduce the likelihood of graft-versus-host disease.

Previous research showed that targeting a CAR to the TRAC locus results in uniform CAR expression and enhances T-cell potency. In fact, TRAC-CAR T cells outperformed conventionally generated CAR T cells by preventing T-cell exhaustion in a mouse model of acute lymphoblastic leukemia.

In vitro experiments

With the current work, the researchers found that FT819 displayed an efficient cytotoxic T-cell response when challenged with CD19-positive tumor cells. FT819 produced cytokines (IFN-gamma, TNF-alpha, and IL-2) and mediators of cell death (CD107a/b, perforin, and granzyme B).

FT819 was also target-specific, attacking only CD19-positive tumor cells and sparing CD19-negative tumor cells in experiments with Raji (Burkitt lymphoma) and Nalm-6 (B-cell acute lymphoblastic leukemia) cell lines.

The researchers said they observed consistent antigen-specific cytotoxicity against Nalm-6 cells with FT819 but variability in antigen-specific cytotoxicity with conventional CAR T cells.

In addition, when combined with rituximab, FT819 elicited antibody-dependent cell-mediated cytotoxicity against CD19-negative, CD20-positive tumor cells.

“Through the development of FT819, we believe there is significant opportunity to lower the cost of CAR T-cell manufacture, enhance the quality of the product, and create a readily available supply of a more efficacious product to reach more patients in need,” Dr Valamehr said.

Photo by Darren Baker

The European Bioinformatics Institute (EMBL-EBI) and The Jackson Laboratory (JAX) have developed an open cancer research portal for patient-derived xenograft (PDX) models.

The portal, known as PDX Finder, catalogues PDX models from numerous global repositories.

At present, PDX Finder contains more than 1900 models for a range of cancers, including hematologic malignancies.

Researchers can search for PDX models and submit their own on the PDX Finder website: http://www.pdxfinder.org.

“PDX models are increasingly recognized as clinically relevant because they retain the patient tumor characteristics and imitate a specific patient’s response to drugs more accurately than other models,” said Nathalie Conte, PDX Finder project lead at EMBL-EBI.

“However, until now, there was no open central catalogue for PDX models. PDX Finder enables cancer researchers to search through a wider variety of models more quickly, saving valuable time and enabling collaborations.”

PDX Finder builds on JAX’s PDX resource, which was developed in partnership with more than 20 medical centers in the US, and EMBL-EBI’s membership of EurOPDX. This ensures the scope and reach of PDX Finder is wider than any other individual resource available, according to JAX and EMBL-EBI.

“Both EMBL-EBI and JAX received independent funding from the National Cancer Institute [NCI] for projects that included implementation of online catalogues for PDX models,” noted Carol Bult, scientific director of the JAX PDX resource.

“Both groups had the goal to help basic and clinical cancer researchers find relevant models fast. With approval from the NCI, we instead collaborated to build a single, unified portal with international scope.”

The launch of PDX Finder comes just months after EMBL-EBI and JAX published the PDX minimal information standard, which sets standards for basic information needed to describe essential properties of a PDX model.

The standard ensures that every model in PDX Finder is carefully described to help researchers choose models that are most relevant to their work.

Photo by Darren Baker

The European Bioinformatics Institute (EMBL-EBI) and The Jackson Laboratory (JAX) have developed an open cancer research portal for patient-derived xenograft (PDX) models.

The portal, known as PDX Finder, catalogues PDX models from numerous global repositories.

At present, PDX Finder contains more than 1900 models for a range of cancers, including hematologic malignancies.

Researchers can search for PDX models and submit their own on the PDX Finder website: http://www.pdxfinder.org.

“PDX models are increasingly recognized as clinically relevant because they retain the patient tumor characteristics and imitate a specific patient’s response to drugs more accurately than other models,” said Nathalie Conte, PDX Finder project lead at EMBL-EBI.

“However, until now, there was no open central catalogue for PDX models. PDX Finder enables cancer researchers to search through a wider variety of models more quickly, saving valuable time and enabling collaborations.”

PDX Finder builds on JAX’s PDX resource, which was developed in partnership with more than 20 medical centers in the US, and EMBL-EBI’s membership of EurOPDX. This ensures the scope and reach of PDX Finder is wider than any other individual resource available, according to JAX and EMBL-EBI.

“Both EMBL-EBI and JAX received independent funding from the National Cancer Institute [NCI] for projects that included implementation of online catalogues for PDX models,” noted Carol Bult, scientific director of the JAX PDX resource.

“Both groups had the goal to help basic and clinical cancer researchers find relevant models fast. With approval from the NCI, we instead collaborated to build a single, unified portal with international scope.”

The launch of PDX Finder comes just months after EMBL-EBI and JAX published the PDX minimal information standard, which sets standards for basic information needed to describe essential properties of a PDX model.

The standard ensures that every model in PDX Finder is carefully described to help researchers choose models that are most relevant to their work.

Photo by Darren Baker

The European Bioinformatics Institute (EMBL-EBI) and The Jackson Laboratory (JAX) have developed an open cancer research portal for patient-derived xenograft (PDX) models.

The portal, known as PDX Finder, catalogues PDX models from numerous global repositories.

At present, PDX Finder contains more than 1900 models for a range of cancers, including hematologic malignancies.

Researchers can search for PDX models and submit their own on the PDX Finder website: http://www.pdxfinder.org.

“PDX models are increasingly recognized as clinically relevant because they retain the patient tumor characteristics and imitate a specific patient’s response to drugs more accurately than other models,” said Nathalie Conte, PDX Finder project lead at EMBL-EBI.

“However, until now, there was no open central catalogue for PDX models. PDX Finder enables cancer researchers to search through a wider variety of models more quickly, saving valuable time and enabling collaborations.”

PDX Finder builds on JAX’s PDX resource, which was developed in partnership with more than 20 medical centers in the US, and EMBL-EBI’s membership of EurOPDX. This ensures the scope and reach of PDX Finder is wider than any other individual resource available, according to JAX and EMBL-EBI.

“Both EMBL-EBI and JAX received independent funding from the National Cancer Institute [NCI] for projects that included implementation of online catalogues for PDX models,” noted Carol Bult, scientific director of the JAX PDX resource.

“Both groups had the goal to help basic and clinical cancer researchers find relevant models fast. With approval from the NCI, we instead collaborated to build a single, unified portal with international scope.”

The launch of PDX Finder comes just months after EMBL-EBI and JAX published the PDX minimal information standard, which sets standards for basic information needed to describe essential properties of a PDX model.

The standard ensures that every model in PDX Finder is carefully described to help researchers choose models that are most relevant to their work.

Berlowitz, D.R., et al, N Engl J Med 377(8):733, August 24, 2017

BACKGROUND: The Systolic Blood Pressure Intervention Trial (SPRINT) showed that a systolic blood pressure (SBP) target lower than 120 mm Hg (intensive treatment) led to lower rates of cardiovascular morbidity and mortality than a 140 mm Hg target (standard treatment). The impact of intensive treatment on patient-reported outcomes is unknown.

METHODS: This study coordinated at the Bedford (MA) Veterans Affairs Hospital assessed patient perceptions using data from SPRINT, a multicenter (n=102) trial of adults aged 50 or older with hypertension at baseline (SBP 130-180 mm Hg) and increased cardiovascular risk but without a history of diabetes or stroke who were randomized to intensive treatment (n=4678) or standard treatment (n=4683). Study endpoints were the Veterans RAND 12-Item Health Survey (Physical Component Summary score [PCS] and Mental Component Summary score [MCS] of 0-100, with higher scores indicating better health), Patient Health Questionnaire 9-item depression scale (PHQ-9, scored 0-27 with higher scores indicating worse depression), 5-point scale for patient satisfaction (from very satisfied to very dissatisfied), and 8-item scale for treatment adherence (with higher scores indicating better adherence).

RESULTS: SBP was 139.7 mm Hg at baseline, 121.4 mm Hg after intensive treatment, and 136.2 mm Hg after standard treatment. Baseline PCS was 44.6 and 44.8, respectively; MCS was 53.2 and 53.1; and PHQ-9 was 3.1 in both groups. Scores were stable and similar between groups throughout three years of follow-up, regardless of age and physical and cognitive function. Both groups were satisfied or very satisfied with their care (88% each), and adherence was similar (score of 8 in 44% each).

CONCLUSIONS: Patient-reported outcomes were similar with intensive versus standard SBP treatment among patients participating in SPRINT. 34 references ([email protected] for reprints)

Berlowitz, D.R., et al, N Engl J Med 377(8):733, August 24, 2017

BACKGROUND: The Systolic Blood Pressure Intervention Trial (SPRINT) showed that a systolic blood pressure (SBP) target lower than 120 mm Hg (intensive treatment) led to lower rates of cardiovascular morbidity and mortality than a 140 mm Hg target (standard treatment). The impact of intensive treatment on patient-reported outcomes is unknown.

METHODS: This study coordinated at the Bedford (MA) Veterans Affairs Hospital assessed patient perceptions using data from SPRINT, a multicenter (n=102) trial of adults aged 50 or older with hypertension at baseline (SBP 130-180 mm Hg) and increased cardiovascular risk but without a history of diabetes or stroke who were randomized to intensive treatment (n=4678) or standard treatment (n=4683). Study endpoints were the Veterans RAND 12-Item Health Survey (Physical Component Summary score [PCS] and Mental Component Summary score [MCS] of 0-100, with higher scores indicating better health), Patient Health Questionnaire 9-item depression scale (PHQ-9, scored 0-27 with higher scores indicating worse depression), 5-point scale for patient satisfaction (from very satisfied to very dissatisfied), and 8-item scale for treatment adherence (with higher scores indicating better adherence).

RESULTS: SBP was 139.7 mm Hg at baseline, 121.4 mm Hg after intensive treatment, and 136.2 mm Hg after standard treatment. Baseline PCS was 44.6 and 44.8, respectively; MCS was 53.2 and 53.1; and PHQ-9 was 3.1 in both groups. Scores were stable and similar between groups throughout three years of follow-up, regardless of age and physical and cognitive function. Both groups were satisfied or very satisfied with their care (88% each), and adherence was similar (score of 8 in 44% each).

CONCLUSIONS: Patient-reported outcomes were similar with intensive versus standard SBP treatment among patients participating in SPRINT. 34 references ([email protected] for reprints)

Berlowitz, D.R., et al, N Engl J Med 377(8):733, August 24, 2017

BACKGROUND: The Systolic Blood Pressure Intervention Trial (SPRINT) showed that a systolic blood pressure (SBP) target lower than 120 mm Hg (intensive treatment) led to lower rates of cardiovascular morbidity and mortality than a 140 mm Hg target (standard treatment). The impact of intensive treatment on patient-reported outcomes is unknown.

METHODS: This study coordinated at the Bedford (MA) Veterans Affairs Hospital assessed patient perceptions using data from SPRINT, a multicenter (n=102) trial of adults aged 50 or older with hypertension at baseline (SBP 130-180 mm Hg) and increased cardiovascular risk but without a history of diabetes or stroke who were randomized to intensive treatment (n=4678) or standard treatment (n=4683). Study endpoints were the Veterans RAND 12-Item Health Survey (Physical Component Summary score [PCS] and Mental Component Summary score [MCS] of 0-100, with higher scores indicating better health), Patient Health Questionnaire 9-item depression scale (PHQ-9, scored 0-27 with higher scores indicating worse depression), 5-point scale for patient satisfaction (from very satisfied to very dissatisfied), and 8-item scale for treatment adherence (with higher scores indicating better adherence).

RESULTS: SBP was 139.7 mm Hg at baseline, 121.4 mm Hg after intensive treatment, and 136.2 mm Hg after standard treatment. Baseline PCS was 44.6 and 44.8, respectively; MCS was 53.2 and 53.1; and PHQ-9 was 3.1 in both groups. Scores were stable and similar between groups throughout three years of follow-up, regardless of age and physical and cognitive function. Both groups were satisfied or very satisfied with their care (88% each), and adherence was similar (score of 8 in 44% each).

CONCLUSIONS: Patient-reported outcomes were similar with intensive versus standard SBP treatment among patients participating in SPRINT. 34 references ([email protected] for reprints)

Clinical question: Do either intravenous sodium bicarbonate or oral acetylcysteine prevent renal morbidity and mortality in patients with chronic kidney disease (CKD) undergoing angiography?

Background: Both intravenous sodium bicarbonate and acetylcysteine are commonly used therapies aimed at preventing contrast-induced nephropathy. However, data regarding their efficacy are controversial, and prior studies have largely included patients with normal renal function.

Dr. Lusa is assistant professor of medicine, division of hospital medicine, University of Virginia.
 

Clinical question: Do either intravenous sodium bicarbonate or oral acetylcysteine prevent renal morbidity and mortality in patients with chronic kidney disease (CKD) undergoing angiography?

Background: Both intravenous sodium bicarbonate and acetylcysteine are commonly used therapies aimed at preventing contrast-induced nephropathy. However, data regarding their efficacy are controversial, and prior studies have largely included patients with normal renal function.

Dr. Lusa is assistant professor of medicine, division of hospital medicine, University of Virginia.
 

Clinical question: Do either intravenous sodium bicarbonate or oral acetylcysteine prevent renal morbidity and mortality in patients with chronic kidney disease (CKD) undergoing angiography?

Background: Both intravenous sodium bicarbonate and acetylcysteine are commonly used therapies aimed at preventing contrast-induced nephropathy. However, data regarding their efficacy are controversial, and prior studies have largely included patients with normal renal function.

Dr. Lusa is assistant professor of medicine, division of hospital medicine, University of Virginia.
 

The Food and Drug Administration has approved osimertinib for the first-line treatment of patients with metastatic non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, as detected by an FDA-approved test.

The drug was approved a year ago for treating those with advanced EGFR-mutated NSCLC and progression following EGFR tyrosine kinase inhibitor therapy.

Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

The Food and Drug Administration has approved osimertinib for the first-line treatment of patients with metastatic non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, as detected by an FDA-approved test.

The drug was approved a year ago for treating those with advanced EGFR-mutated NSCLC and progression following EGFR tyrosine kinase inhibitor therapy.

Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

The Food and Drug Administration has approved osimertinib for the first-line treatment of patients with metastatic non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, as detected by an FDA-approved test.

The drug was approved a year ago for treating those with advanced EGFR-mutated NSCLC and progression following EGFR tyrosine kinase inhibitor therapy.

Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

Physicians and nurses turn to a wide variety of kinds of dressings to treat patients with diabetic foot ulcers (DFU). Now, new data from an industry-funded study suggest that an experimental nitric oxide-generating dressing holds promise as a tool to reduce diabetic foot wound size in certain cases.

Balkonsky/Thinkstock

The treatment is still in the research stage, and it’s not clear whether more studies will be conducted. For now, though, “we have a topical agent which specifically treats infection as well as increases perfusion of the ulcer,” study lead author Michael E. Edmonds, MD, a professor of diabetes and endocrinology at King’s College Hospital in London, said in an interview. “The study also showed that the agent not only improved healing but significantly reduced serious adverse events related to the ulcer, which included hospitalizations and amputations.”
 

The study appeared online April 4 in Wound Repair and Regeneration.

Researchers estimate that DFUs affect as many as 4% of patients with diabetes each year, with about a quarter developing the condition over their lifetimes.

A 2014 U.S. study found that 4%-5% percentage of patients with DFUs underwent lower limb amputations over a 12-month period. The same study also estimated that DFU-related care costs as much as $13 billion a year. (Diabetes Care. 2014 Mar;37[3]:651-8)

“There is no straightforward guideline to choose dressing,” said wound care specialist William H. Tettelbach, MD, the medical director of infection prevention, wound care, and antibiotic stewardship at Landmark Hospital in Salt Lake City, in an interview. Instead, he said, there are just some general tenets: Use an absorbing dressing for a wet ulcer, a moist dressing for a dry ulcer, and an antimicrobial dressing for a bacterial ulcer.

The new multi-center, randomized, controlled phase 2/3 study – funded by the biotech company Edixomed – examined the use of a nitric oxide–generating dressing known as EDX110. The dressing consists of a moist mesh and a second layer that keeps the first layer in place.

“The critical factors that delay the healing of diabetic foot ulcers are ischemia and infection,” Dr. Edmonds said. “Nitric oxide plays a crucial role in maintaining the microvascular supply and infection control in the skin, and its absence in diabetes contributes to poor ulcer healing. EDX110 generates a sustained release of nitric oxide which can treat both infection and ischemia simultaneously.”

The institutes used a wide variety of dressings including absorbent pad, alginate, antimicrobial, foam, gauze, and other types. About a third were antimicrobial.

In the intent-to-treat population at 12 weeks, the median percentage area reduction of the ulcers was 89% in the treatment group, compared with 47% in the control group (P = .016).

The researchers reported significantly fewer serious adverse events in the treatment group, and none were reported to be linked to the various dressings used.

According to Dr. Edmonds, pricing information for the treatment is unavailable.

Dr. Tettelbach cautioned about the limitations of the study. For one, it doesn’t focus on chronic DFUs that can last well beyond a month and “are more problematic to heal and pose a greater relative risk of infection than acute DFUs.”

He added: “Surrogate end points such as 80% reduction in surface area at 12 weeks are difficult to extrapolate to expected closure. An open chronic ulcer is at risk for complicating infection no matter what size,” he said.

Overall, Dr. Tettelbach said, he doesn’t see the study as a “big deal,” but it’s “a welcomed addition to the wound dressing family that works using a novel mechanism of stimulating angiogenesis and antimicrobial properties.”

The biotech company Edixomed funded the study. The study authors report various disclosures or no disclosures; two disclose links to Edixomed.

SOURCE: Edmonds ME et al. Wound Repair Regen. 2018 April 4. doi: 10.1111/wrr.12630.

Physicians and nurses turn to a wide variety of kinds of dressings to treat patients with diabetic foot ulcers (DFU). Now, new data from an industry-funded study suggest that an experimental nitric oxide-generating dressing holds promise as a tool to reduce diabetic foot wound size in certain cases.

Balkonsky/Thinkstock

The treatment is still in the research stage, and it’s not clear whether more studies will be conducted. For now, though, “we have a topical agent which specifically treats infection as well as increases perfusion of the ulcer,” study lead author Michael E. Edmonds, MD, a professor of diabetes and endocrinology at King’s College Hospital in London, said in an interview. “The study also showed that the agent not only improved healing but significantly reduced serious adverse events related to the ulcer, which included hospitalizations and amputations.”
 

The study appeared online April 4 in Wound Repair and Regeneration.

Researchers estimate that DFUs affect as many as 4% of patients with diabetes each year, with about a quarter developing the condition over their lifetimes.

A 2014 U.S. study found that 4%-5% percentage of patients with DFUs underwent lower limb amputations over a 12-month period. The same study also estimated that DFU-related care costs as much as $13 billion a year. (Diabetes Care. 2014 Mar;37[3]:651-8)

“There is no straightforward guideline to choose dressing,” said wound care specialist William H. Tettelbach, MD, the medical director of infection prevention, wound care, and antibiotic stewardship at Landmark Hospital in Salt Lake City, in an interview. Instead, he said, there are just some general tenets: Use an absorbing dressing for a wet ulcer, a moist dressing for a dry ulcer, and an antimicrobial dressing for a bacterial ulcer.

The new multi-center, randomized, controlled phase 2/3 study – funded by the biotech company Edixomed – examined the use of a nitric oxide–generating dressing known as EDX110. The dressing consists of a moist mesh and a second layer that keeps the first layer in place.

“The critical factors that delay the healing of diabetic foot ulcers are ischemia and infection,” Dr. Edmonds said. “Nitric oxide plays a crucial role in maintaining the microvascular supply and infection control in the skin, and its absence in diabetes contributes to poor ulcer healing. EDX110 generates a sustained release of nitric oxide which can treat both infection and ischemia simultaneously.”

The institutes used a wide variety of dressings including absorbent pad, alginate, antimicrobial, foam, gauze, and other types. About a third were antimicrobial.

In the intent-to-treat population at 12 weeks, the median percentage area reduction of the ulcers was 89% in the treatment group, compared with 47% in the control group (P = .016).

The researchers reported significantly fewer serious adverse events in the treatment group, and none were reported to be linked to the various dressings used.

According to Dr. Edmonds, pricing information for the treatment is unavailable.

Dr. Tettelbach cautioned about the limitations of the study. For one, it doesn’t focus on chronic DFUs that can last well beyond a month and “are more problematic to heal and pose a greater relative risk of infection than acute DFUs.”

He added: “Surrogate end points such as 80% reduction in surface area at 12 weeks are difficult to extrapolate to expected closure. An open chronic ulcer is at risk for complicating infection no matter what size,” he said.

Overall, Dr. Tettelbach said, he doesn’t see the study as a “big deal,” but it’s “a welcomed addition to the wound dressing family that works using a novel mechanism of stimulating angiogenesis and antimicrobial properties.”

The biotech company Edixomed funded the study. The study authors report various disclosures or no disclosures; two disclose links to Edixomed.

SOURCE: Edmonds ME et al. Wound Repair Regen. 2018 April 4. doi: 10.1111/wrr.12630.

Physicians and nurses turn to a wide variety of kinds of dressings to treat patients with diabetic foot ulcers (DFU). Now, new data from an industry-funded study suggest that an experimental nitric oxide-generating dressing holds promise as a tool to reduce diabetic foot wound size in certain cases.

Balkonsky/Thinkstock

The treatment is still in the research stage, and it’s not clear whether more studies will be conducted. For now, though, “we have a topical agent which specifically treats infection as well as increases perfusion of the ulcer,” study lead author Michael E. Edmonds, MD, a professor of diabetes and endocrinology at King’s College Hospital in London, said in an interview. “The study also showed that the agent not only improved healing but significantly reduced serious adverse events related to the ulcer, which included hospitalizations and amputations.”
 

The study appeared online April 4 in Wound Repair and Regeneration.

Researchers estimate that DFUs affect as many as 4% of patients with diabetes each year, with about a quarter developing the condition over their lifetimes.

A 2014 U.S. study found that 4%-5% percentage of patients with DFUs underwent lower limb amputations over a 12-month period. The same study also estimated that DFU-related care costs as much as $13 billion a year. (Diabetes Care. 2014 Mar;37[3]:651-8)

“There is no straightforward guideline to choose dressing,” said wound care specialist William H. Tettelbach, MD, the medical director of infection prevention, wound care, and antibiotic stewardship at Landmark Hospital in Salt Lake City, in an interview. Instead, he said, there are just some general tenets: Use an absorbing dressing for a wet ulcer, a moist dressing for a dry ulcer, and an antimicrobial dressing for a bacterial ulcer.

The new multi-center, randomized, controlled phase 2/3 study – funded by the biotech company Edixomed – examined the use of a nitric oxide–generating dressing known as EDX110. The dressing consists of a moist mesh and a second layer that keeps the first layer in place.

“The critical factors that delay the healing of diabetic foot ulcers are ischemia and infection,” Dr. Edmonds said. “Nitric oxide plays a crucial role in maintaining the microvascular supply and infection control in the skin, and its absence in diabetes contributes to poor ulcer healing. EDX110 generates a sustained release of nitric oxide which can treat both infection and ischemia simultaneously.”

The institutes used a wide variety of dressings including absorbent pad, alginate, antimicrobial, foam, gauze, and other types. About a third were antimicrobial.

In the intent-to-treat population at 12 weeks, the median percentage area reduction of the ulcers was 89% in the treatment group, compared with 47% in the control group (P = .016).

The researchers reported significantly fewer serious adverse events in the treatment group, and none were reported to be linked to the various dressings used.

According to Dr. Edmonds, pricing information for the treatment is unavailable.

Dr. Tettelbach cautioned about the limitations of the study. For one, it doesn’t focus on chronic DFUs that can last well beyond a month and “are more problematic to heal and pose a greater relative risk of infection than acute DFUs.”

He added: “Surrogate end points such as 80% reduction in surface area at 12 weeks are difficult to extrapolate to expected closure. An open chronic ulcer is at risk for complicating infection no matter what size,” he said.

Overall, Dr. Tettelbach said, he doesn’t see the study as a “big deal,” but it’s “a welcomed addition to the wound dressing family that works using a novel mechanism of stimulating angiogenesis and antimicrobial properties.”

The biotech company Edixomed funded the study. The study authors report various disclosures or no disclosures; two disclose links to Edixomed.

SOURCE: Edmonds ME et al. Wound Repair Regen. 2018 April 4. doi: 10.1111/wrr.12630.