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Doc provides perspective on CAR T-cell therapy in CLL
Photo from Penn Medicine
NEW YORK—Trial data on the use of chimeric antigen receptor (CAR) T cells in chronic lymphocytic leukemia (CLL) are maturing, and a speaker at Lymphoma & Myeloma 2016 provided some perspective on the therapy as it now stands.
Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, noted that some CLL patients treated with CAR T cells remain in complete remission (CR) for more than 5 years.
Therefore, CAR T cells may be a consideration for patients who are resistant to chemotherapy.
“[I]mportantly, this immunologic approach, like other immunologic approaches . . ., tends to be non-cross-resistant to chemotherapy,” Dr Schuster said.
He made these and other observations while discussing trials of CAR T-cell therapy (particularly CTL019) in CLL.
Pilot study of CTL019 in CLL
CTL019, which is the CAR T-cell therapy used by investigators at the University of Pennsylvania, is licensed to Novartis.
The pilot study of CTL019, begun in 2009, enrolled 14 patients who had failed at least 2 prior therapies and progressed within 2 years of their last treatment.
Four patients (29%) achieved a CR, and 4 (29%) achieved a partial response (PR), for an overall response rate of 57%. Detailed results from this trial were reported earlier in HematologyTimes.
Two patients in this trial are still in CR beyond 5 years.
When investigators analyzed the different variables that might affect response—including age, number of prior therapies, p53 status, CAR T-cell dose, and the presence of cytokine release syndrome (CRS)—2 things became apparent.
First, patients who responded tended to have greater in vivo expansion of the CAR T cells than non-responders. And second, the responders had a greater incidence of CRS than non-responders.
Additionally, complete responders were negative for minimal residual disease (MRD) and had durable responses.
“This actually is different from the data you see in lymphoma with CAR cells,” Dr Schuster said. “[However,] it’s what we see in ALL [acute lymphoblastic leukemia] as well.”
Investigators also discovered that persistence of CAR T cells correlates with B-cell aplasia. In this trial, persistence of CAR T cells and B-cell aplasia were apparent at 12 and 18 months, and, in some cases, even longer.
“This is in distinction to what we are observing in trials with the lymphomas,” Dr Schuster said. “So what’s going to emerge is that the different diseases will have different response rates, different degrees of persistence of CAR cells and different toxicities.”
“When we compare B-cell ALL, B-cell non-Hodgkin lymphomas, you’ll get different responses across the subtypes of lymphomas, some unique toxicities, and differences in CLL. So these are all different diseases.”
Dose-finding trial of CTL019 in CLL
The second trial of CTL019 in relapsed/refractory CLL patients was a dose-finding study. Updated results from this study were presented at ASCO 2016.
The high-dose arm (5x108 CTL019) had a 10 times higher dose of CAR T cells than the low-dose arm (5x107 CTL019).
Investigators treated 12 patients in each arm in the first phase of the study, and then expanded the trial to include another 8 patients at the recommended dose. The phase 2 trial was powered for response rates but not duration of response.
Twenty-eight patients were enrolled, with 24 evaluable, 11 in the high-dose arm and 13 in the low-dose arm.
Their median age was 62 (range, 51-75), the median number of prior therapies was 4 (range, 2–7), 38% had p53 deletion, and 12% had received prior ibrutinib therapy.
With the 2 arms pooled together, 25% of patients achieved a CR, and 17% achieved a PR, for an overall response rate of 42%.
“Toxicities were identical in each group,” Dr Schuster said.
He noted that the CRS rate was “fairly high.” The incidence was 55% in the high-dose arm and 54% in the low-dose arm.
There was a tendency, although not statistically significant, for the higher-dose patients to have a greater response rate than the lower-dose group—54% and 31%, respectively.
So the investigators decided the expansion cohort should be conducted with the higher dose, “even though we weren’t sure there really was a difference,” Dr Schuster said.
Seventeen evaluable patients received the higher dose in the expansion cohort. Six (35%) achieved a CR, and 3 (18%) achieved a PR, for an overall response rate of 53%.
“Most [adverse] events happen in the first 3 months,” after infusion, Dr Schuster said. “And then nothing much happens. That’s because the patients that are responsive to this therapy have durable responses.”
Of all the patients who achieved a CR, only 2 have relapsed, he said, “and now many of these patients have passed the 5-year mark for complete remissions.”
Toxicity of CTL019 in CLL
“When you give the cells, there’s not much toxicity,” Dr Schuster said. “These are the patients’ own cells; they’re not reacting adversely to that. It’s what happens afterwards that you have to be on the lookout for as the cells begin to expand in vivo.”
Patients experience some reversible renal toxicity, mostly hypertension-related, and some tumor lysis syndrome (TLS). No deaths occurred from TLS in CLL.
B-cell aplasia and hypogammaglobulinema occur in responding patients. They receive gamma globulin replacement as supportive therapy and generally experience no excessive or unusual infections.
“Cytokine release syndrome is the real thing to look at,” Dr Schuster said, “and that’s where early recognition and management will be life-saving.”
In both CLL and ALL, almost all responding patients develop CRS, which can be rapidly reversed with tocilizumab, the IL-6 receptor blocker.
Other CAR T-cell trials in CLL
Institutions other than the University of Pennsylvania have conducted trials of CAR T-cell therapies other than CTL019, and response rates in CLL patients have ranged from 25% (MSKCC) to 46% (Seattle), as reported at ASCO this year.
“But what’s really important to keep in mind is almost all patients who achieve complete response to date have stayed in complete response,” Dr Schuster said.
Combination trials with ibrutinib
Dr Schuster noted that patients in CAR T-cell trials who had been on ibrutinib for more than 5 months “had really robust T-cell expansion.”
So investigators believe treatment with ibrutinib may be a way of enhancing T-cell function.
A combination trial of ibrutinib and CTL019 is underway (NCT02640209). Six patients have been treated thus far, and although the follow-up is short, all 6 achieved CR at the 3-month assessment.
“So the hope is that this is going to be a partner [therapy],” Dr Schuster said. “And maybe these complete responses will be very durable, like the responses in earlier trials of CAR therapy in patients with CLL.” 
Photo from Penn Medicine
NEW YORK—Trial data on the use of chimeric antigen receptor (CAR) T cells in chronic lymphocytic leukemia (CLL) are maturing, and a speaker at Lymphoma & Myeloma 2016 provided some perspective on the therapy as it now stands.
Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, noted that some CLL patients treated with CAR T cells remain in complete remission (CR) for more than 5 years.
Therefore, CAR T cells may be a consideration for patients who are resistant to chemotherapy.
“[I]mportantly, this immunologic approach, like other immunologic approaches . . ., tends to be non-cross-resistant to chemotherapy,” Dr Schuster said.
He made these and other observations while discussing trials of CAR T-cell therapy (particularly CTL019) in CLL.
Pilot study of CTL019 in CLL
CTL019, which is the CAR T-cell therapy used by investigators at the University of Pennsylvania, is licensed to Novartis.
The pilot study of CTL019, begun in 2009, enrolled 14 patients who had failed at least 2 prior therapies and progressed within 2 years of their last treatment.
Four patients (29%) achieved a CR, and 4 (29%) achieved a partial response (PR), for an overall response rate of 57%. Detailed results from this trial were reported earlier in HematologyTimes.
Two patients in this trial are still in CR beyond 5 years.
When investigators analyzed the different variables that might affect response—including age, number of prior therapies, p53 status, CAR T-cell dose, and the presence of cytokine release syndrome (CRS)—2 things became apparent.
First, patients who responded tended to have greater in vivo expansion of the CAR T cells than non-responders. And second, the responders had a greater incidence of CRS than non-responders.
Additionally, complete responders were negative for minimal residual disease (MRD) and had durable responses.
“This actually is different from the data you see in lymphoma with CAR cells,” Dr Schuster said. “[However,] it’s what we see in ALL [acute lymphoblastic leukemia] as well.”
Investigators also discovered that persistence of CAR T cells correlates with B-cell aplasia. In this trial, persistence of CAR T cells and B-cell aplasia were apparent at 12 and 18 months, and, in some cases, even longer.
“This is in distinction to what we are observing in trials with the lymphomas,” Dr Schuster said. “So what’s going to emerge is that the different diseases will have different response rates, different degrees of persistence of CAR cells and different toxicities.”
“When we compare B-cell ALL, B-cell non-Hodgkin lymphomas, you’ll get different responses across the subtypes of lymphomas, some unique toxicities, and differences in CLL. So these are all different diseases.”
Dose-finding trial of CTL019 in CLL
The second trial of CTL019 in relapsed/refractory CLL patients was a dose-finding study. Updated results from this study were presented at ASCO 2016.
The high-dose arm (5x108 CTL019) had a 10 times higher dose of CAR T cells than the low-dose arm (5x107 CTL019).
Investigators treated 12 patients in each arm in the first phase of the study, and then expanded the trial to include another 8 patients at the recommended dose. The phase 2 trial was powered for response rates but not duration of response.
Twenty-eight patients were enrolled, with 24 evaluable, 11 in the high-dose arm and 13 in the low-dose arm.
Their median age was 62 (range, 51-75), the median number of prior therapies was 4 (range, 2–7), 38% had p53 deletion, and 12% had received prior ibrutinib therapy.
With the 2 arms pooled together, 25% of patients achieved a CR, and 17% achieved a PR, for an overall response rate of 42%.
“Toxicities were identical in each group,” Dr Schuster said.
He noted that the CRS rate was “fairly high.” The incidence was 55% in the high-dose arm and 54% in the low-dose arm.
There was a tendency, although not statistically significant, for the higher-dose patients to have a greater response rate than the lower-dose group—54% and 31%, respectively.
So the investigators decided the expansion cohort should be conducted with the higher dose, “even though we weren’t sure there really was a difference,” Dr Schuster said.
Seventeen evaluable patients received the higher dose in the expansion cohort. Six (35%) achieved a CR, and 3 (18%) achieved a PR, for an overall response rate of 53%.
“Most [adverse] events happen in the first 3 months,” after infusion, Dr Schuster said. “And then nothing much happens. That’s because the patients that are responsive to this therapy have durable responses.”
Of all the patients who achieved a CR, only 2 have relapsed, he said, “and now many of these patients have passed the 5-year mark for complete remissions.”
Toxicity of CTL019 in CLL
“When you give the cells, there’s not much toxicity,” Dr Schuster said. “These are the patients’ own cells; they’re not reacting adversely to that. It’s what happens afterwards that you have to be on the lookout for as the cells begin to expand in vivo.”
Patients experience some reversible renal toxicity, mostly hypertension-related, and some tumor lysis syndrome (TLS). No deaths occurred from TLS in CLL.
B-cell aplasia and hypogammaglobulinema occur in responding patients. They receive gamma globulin replacement as supportive therapy and generally experience no excessive or unusual infections.
“Cytokine release syndrome is the real thing to look at,” Dr Schuster said, “and that’s where early recognition and management will be life-saving.”
In both CLL and ALL, almost all responding patients develop CRS, which can be rapidly reversed with tocilizumab, the IL-6 receptor blocker.
Other CAR T-cell trials in CLL
Institutions other than the University of Pennsylvania have conducted trials of CAR T-cell therapies other than CTL019, and response rates in CLL patients have ranged from 25% (MSKCC) to 46% (Seattle), as reported at ASCO this year.
“But what’s really important to keep in mind is almost all patients who achieve complete response to date have stayed in complete response,” Dr Schuster said.
Combination trials with ibrutinib
Dr Schuster noted that patients in CAR T-cell trials who had been on ibrutinib for more than 5 months “had really robust T-cell expansion.”
So investigators believe treatment with ibrutinib may be a way of enhancing T-cell function.
A combination trial of ibrutinib and CTL019 is underway (NCT02640209). Six patients have been treated thus far, and although the follow-up is short, all 6 achieved CR at the 3-month assessment.
“So the hope is that this is going to be a partner [therapy],” Dr Schuster said. “And maybe these complete responses will be very durable, like the responses in earlier trials of CAR therapy in patients with CLL.”
Photo from Penn Medicine
NEW YORK—Trial data on the use of chimeric antigen receptor (CAR) T cells in chronic lymphocytic leukemia (CLL) are maturing, and a speaker at Lymphoma & Myeloma 2016 provided some perspective on the therapy as it now stands.
Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, noted that some CLL patients treated with CAR T cells remain in complete remission (CR) for more than 5 years.
Therefore, CAR T cells may be a consideration for patients who are resistant to chemotherapy.
“[I]mportantly, this immunologic approach, like other immunologic approaches . . ., tends to be non-cross-resistant to chemotherapy,” Dr Schuster said.
He made these and other observations while discussing trials of CAR T-cell therapy (particularly CTL019) in CLL.
Pilot study of CTL019 in CLL
CTL019, which is the CAR T-cell therapy used by investigators at the University of Pennsylvania, is licensed to Novartis.
The pilot study of CTL019, begun in 2009, enrolled 14 patients who had failed at least 2 prior therapies and progressed within 2 years of their last treatment.
Four patients (29%) achieved a CR, and 4 (29%) achieved a partial response (PR), for an overall response rate of 57%. Detailed results from this trial were reported earlier in HematologyTimes.
Two patients in this trial are still in CR beyond 5 years.
When investigators analyzed the different variables that might affect response—including age, number of prior therapies, p53 status, CAR T-cell dose, and the presence of cytokine release syndrome (CRS)—2 things became apparent.
First, patients who responded tended to have greater in vivo expansion of the CAR T cells than non-responders. And second, the responders had a greater incidence of CRS than non-responders.
Additionally, complete responders were negative for minimal residual disease (MRD) and had durable responses.
“This actually is different from the data you see in lymphoma with CAR cells,” Dr Schuster said. “[However,] it’s what we see in ALL [acute lymphoblastic leukemia] as well.”
Investigators also discovered that persistence of CAR T cells correlates with B-cell aplasia. In this trial, persistence of CAR T cells and B-cell aplasia were apparent at 12 and 18 months, and, in some cases, even longer.
“This is in distinction to what we are observing in trials with the lymphomas,” Dr Schuster said. “So what’s going to emerge is that the different diseases will have different response rates, different degrees of persistence of CAR cells and different toxicities.”
“When we compare B-cell ALL, B-cell non-Hodgkin lymphomas, you’ll get different responses across the subtypes of lymphomas, some unique toxicities, and differences in CLL. So these are all different diseases.”
Dose-finding trial of CTL019 in CLL
The second trial of CTL019 in relapsed/refractory CLL patients was a dose-finding study. Updated results from this study were presented at ASCO 2016.
The high-dose arm (5x108 CTL019) had a 10 times higher dose of CAR T cells than the low-dose arm (5x107 CTL019).
Investigators treated 12 patients in each arm in the first phase of the study, and then expanded the trial to include another 8 patients at the recommended dose. The phase 2 trial was powered for response rates but not duration of response.
Twenty-eight patients were enrolled, with 24 evaluable, 11 in the high-dose arm and 13 in the low-dose arm.
Their median age was 62 (range, 51-75), the median number of prior therapies was 4 (range, 2–7), 38% had p53 deletion, and 12% had received prior ibrutinib therapy.
With the 2 arms pooled together, 25% of patients achieved a CR, and 17% achieved a PR, for an overall response rate of 42%.
“Toxicities were identical in each group,” Dr Schuster said.
He noted that the CRS rate was “fairly high.” The incidence was 55% in the high-dose arm and 54% in the low-dose arm.
There was a tendency, although not statistically significant, for the higher-dose patients to have a greater response rate than the lower-dose group—54% and 31%, respectively.
So the investigators decided the expansion cohort should be conducted with the higher dose, “even though we weren’t sure there really was a difference,” Dr Schuster said.
Seventeen evaluable patients received the higher dose in the expansion cohort. Six (35%) achieved a CR, and 3 (18%) achieved a PR, for an overall response rate of 53%.
“Most [adverse] events happen in the first 3 months,” after infusion, Dr Schuster said. “And then nothing much happens. That’s because the patients that are responsive to this therapy have durable responses.”
Of all the patients who achieved a CR, only 2 have relapsed, he said, “and now many of these patients have passed the 5-year mark for complete remissions.”
Toxicity of CTL019 in CLL
“When you give the cells, there’s not much toxicity,” Dr Schuster said. “These are the patients’ own cells; they’re not reacting adversely to that. It’s what happens afterwards that you have to be on the lookout for as the cells begin to expand in vivo.”
Patients experience some reversible renal toxicity, mostly hypertension-related, and some tumor lysis syndrome (TLS). No deaths occurred from TLS in CLL.
B-cell aplasia and hypogammaglobulinema occur in responding patients. They receive gamma globulin replacement as supportive therapy and generally experience no excessive or unusual infections.
“Cytokine release syndrome is the real thing to look at,” Dr Schuster said, “and that’s where early recognition and management will be life-saving.”
In both CLL and ALL, almost all responding patients develop CRS, which can be rapidly reversed with tocilizumab, the IL-6 receptor blocker.
Other CAR T-cell trials in CLL
Institutions other than the University of Pennsylvania have conducted trials of CAR T-cell therapies other than CTL019, and response rates in CLL patients have ranged from 25% (MSKCC) to 46% (Seattle), as reported at ASCO this year.
“But what’s really important to keep in mind is almost all patients who achieve complete response to date have stayed in complete response,” Dr Schuster said.
Combination trials with ibrutinib
Dr Schuster noted that patients in CAR T-cell trials who had been on ibrutinib for more than 5 months “had really robust T-cell expansion.”
So investigators believe treatment with ibrutinib may be a way of enhancing T-cell function.
A combination trial of ibrutinib and CTL019 is underway (NCT02640209). Six patients have been treated thus far, and although the follow-up is short, all 6 achieved CR at the 3-month assessment.
“So the hope is that this is going to be a partner [therapy],” Dr Schuster said. “And maybe these complete responses will be very durable, like the responses in earlier trials of CAR therapy in patients with CLL.”
Gene therapy could treat hemophilia A
A new discovery contradicts prevailing assumptions about hemophilia and could change the treatment of hemophilia A, according to researchers.
The team discovered that the protein furin, which is required in factor IX (FIX) replacement, is not required in factor VIII (FVIII) replacement.
In fact, furin impairs clotting in hemophilia A, so gene therapy that can avoid furin processing may provide more effective treatment of hemophilia A.
Experiments in mice and dogs with severe hemophilia A supported this idea. Researchers described the experiments in JCI Insight.
“The clotting factors involved in hemophilia A and hemophilia B are very different, and this has important implications in devising new treatments,” said study author Valder R. Arruda, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.
Dr Arruda and his colleagues noted that biological differences between FVIII and FIX mean there are obstacles to effective gene therapy in hemophilia A that are not an issue in hemophilia B.
Specifically, the gene encoding FIX is much smaller than the gene for FVIII. So the gene encoding FIX is easier to fit into a vector designed to deliver the therapy to a patient.
“In gene therapy, size matters,” Dr Arruda said. “It’s important to reduce the gene package for FVIII to the smallest effective size.”
He added that, according to his group’s research, deleting the furin-recognition components both decreases the size of the gene therapy payload and strengthens its benefits for treating hemophilia A.
Dr Arruda and his colleagues bioengineered a new variant protein, FVIII-ΔF, which avoids interacting with furin. The team then used that variant in gene therapy experiments in animals with severe hemophilia A.
In mice, FVIII-ΔF gene therapy increased recombinant protein yields, enhanced clotting activity, and produced higher circulating FVIII levels when compared to B-domain-deleted FVIII.
In lab dogs with naturally occurring severe hemophilia A, FVIII-ΔF gene therapy decreased bleeding without triggering a higher level of unwanted immune reactions.
“While much work remains to be done to develop this research into clinical applications, our findings could have a promising translational impact, both for protein replacement and gene therapy,” Dr Arruda said.
“Because this variant provides more efficient bleeding control than currently available replacement drugs, while avoiding immune reactions, this could address the unmet needs of hemophilia A patients worldwide. It may also advance gene therapy for this disorder as well.”
A new discovery contradicts prevailing assumptions about hemophilia and could change the treatment of hemophilia A, according to researchers.
The team discovered that the protein furin, which is required in factor IX (FIX) replacement, is not required in factor VIII (FVIII) replacement.
In fact, furin impairs clotting in hemophilia A, so gene therapy that can avoid furin processing may provide more effective treatment of hemophilia A.
Experiments in mice and dogs with severe hemophilia A supported this idea. Researchers described the experiments in JCI Insight.
“The clotting factors involved in hemophilia A and hemophilia B are very different, and this has important implications in devising new treatments,” said study author Valder R. Arruda, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.
Dr Arruda and his colleagues noted that biological differences between FVIII and FIX mean there are obstacles to effective gene therapy in hemophilia A that are not an issue in hemophilia B.
Specifically, the gene encoding FIX is much smaller than the gene for FVIII. So the gene encoding FIX is easier to fit into a vector designed to deliver the therapy to a patient.
“In gene therapy, size matters,” Dr Arruda said. “It’s important to reduce the gene package for FVIII to the smallest effective size.”
He added that, according to his group’s research, deleting the furin-recognition components both decreases the size of the gene therapy payload and strengthens its benefits for treating hemophilia A.
Dr Arruda and his colleagues bioengineered a new variant protein, FVIII-ΔF, which avoids interacting with furin. The team then used that variant in gene therapy experiments in animals with severe hemophilia A.
In mice, FVIII-ΔF gene therapy increased recombinant protein yields, enhanced clotting activity, and produced higher circulating FVIII levels when compared to B-domain-deleted FVIII.
In lab dogs with naturally occurring severe hemophilia A, FVIII-ΔF gene therapy decreased bleeding without triggering a higher level of unwanted immune reactions.
“While much work remains to be done to develop this research into clinical applications, our findings could have a promising translational impact, both for protein replacement and gene therapy,” Dr Arruda said.
“Because this variant provides more efficient bleeding control than currently available replacement drugs, while avoiding immune reactions, this could address the unmet needs of hemophilia A patients worldwide. It may also advance gene therapy for this disorder as well.”
A new discovery contradicts prevailing assumptions about hemophilia and could change the treatment of hemophilia A, according to researchers.
The team discovered that the protein furin, which is required in factor IX (FIX) replacement, is not required in factor VIII (FVIII) replacement.
In fact, furin impairs clotting in hemophilia A, so gene therapy that can avoid furin processing may provide more effective treatment of hemophilia A.
Experiments in mice and dogs with severe hemophilia A supported this idea. Researchers described the experiments in JCI Insight.
“The clotting factors involved in hemophilia A and hemophilia B are very different, and this has important implications in devising new treatments,” said study author Valder R. Arruda, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.
Dr Arruda and his colleagues noted that biological differences between FVIII and FIX mean there are obstacles to effective gene therapy in hemophilia A that are not an issue in hemophilia B.
Specifically, the gene encoding FIX is much smaller than the gene for FVIII. So the gene encoding FIX is easier to fit into a vector designed to deliver the therapy to a patient.
“In gene therapy, size matters,” Dr Arruda said. “It’s important to reduce the gene package for FVIII to the smallest effective size.”
He added that, according to his group’s research, deleting the furin-recognition components both decreases the size of the gene therapy payload and strengthens its benefits for treating hemophilia A.
Dr Arruda and his colleagues bioengineered a new variant protein, FVIII-ΔF, which avoids interacting with furin. The team then used that variant in gene therapy experiments in animals with severe hemophilia A.
In mice, FVIII-ΔF gene therapy increased recombinant protein yields, enhanced clotting activity, and produced higher circulating FVIII levels when compared to B-domain-deleted FVIII.
In lab dogs with naturally occurring severe hemophilia A, FVIII-ΔF gene therapy decreased bleeding without triggering a higher level of unwanted immune reactions.
“While much work remains to be done to develop this research into clinical applications, our findings could have a promising translational impact, both for protein replacement and gene therapy,” Dr Arruda said.
“Because this variant provides more efficient bleeding control than currently available replacement drugs, while avoiding immune reactions, this could address the unmet needs of hemophilia A patients worldwide. It may also advance gene therapy for this disorder as well.”
Work reveals potential therapeutic targets in AML
By adapting CRISPR-Cas9 technology and using it to screen the leukemia genome, researchers have identified hundreds of potential therapeutic targets for acute myeloid leukemia (AML).
The group’s work revealed nearly 500 genes, many of which had not been identified previously, that might serve as targets for AML treatment.
Subsequent experiments showed that targeting one of the genes, KAT2A, can destroy AML cells without harming normal blood cells.
This research was published in Cell Reports.
For this study, the researchers used CRISPR-Cas9 gene-editing technology to screen leukemia cells for vulnerable points. The team said they refined the technology so they could disrupt all genes in the leukemia cell genome individually.
This allowed the researchers to identify those genes whose disruption was detrimental to the growth and survival of AML cells, particularly the AML cell lines MOLM-13, HL-60, OCI-AML2, OCI-AML3, and MV4-11.
“Previous studies showed proof of principle, but this is one of the first systematic attempts to identify the genetic vulnerabilities of AML,” said study author Kosuke Yusa, PhD, of Wellcome Trust Sanger Institute in Hinxton, Cambridge, UK.
“We have improved and applied CRISPR-Cas9 technology to look at what actually kills cells.”
In this way, the researchers identified 492 genes that are essential for AML cell survival, including 227 genes that are druggable.
The team noted that a handful of the genes they identified—including DOT1L, BCL2, and MEN1—are already established therapeutic targets, but most of them are not.
The researchers chose to perform additional experiments with one of the genes they identified, KAT2A, to demonstrate the validity of their findings.
KAT2A was one of 66 genes that were essential to 3 or more of the AML cell lines studied. KAT2A was essential for survival in MOLM-13, OCI-AML2, and OCI-AML3.
The team inhibited KAT2A in vitro using genetic and drug-based techniques. Results showed that disrupting KAT2A inhibited the growth and survival of AML cells but did not affect normal blood cells.
“This is an exciting finding, as KAT2A inhibition worked on a number of primary AML cells with diverse genotypes,” said study author Konstantinos Tzelepis, a PhD student at Wellcome Trust Sanger Institute.
“Whilst the gene needs to be studied in greater depth to understand its potential for use in the clinic, we show that targeting KAT2A destroyed AML cells in the laboratory while sparing healthy blood cells.”
The researchers also targeted KAT2A in transgenic mice. The team observed a significant reduction in AML cell expansion and a significant improvement in survival when KAT2A was disrupted.
“This research has led to the identification of many potential gene targets for future AML therapy, which we are making available to other researchers to explore,” said study author George Vassiliou, PhD, of Wellcome Trust Sanger Institute.
“Whilst KAT2A inhibition now needs to be investigated as a treatment strategy for acute myeloid leukemia, there are many more candidates to pursue by the leukemia research community. Our hope is that this work will lead to more effective treatments against AML that will improve both the survival and the quality of life of patients.”
By adapting CRISPR-Cas9 technology and using it to screen the leukemia genome, researchers have identified hundreds of potential therapeutic targets for acute myeloid leukemia (AML).
The group’s work revealed nearly 500 genes, many of which had not been identified previously, that might serve as targets for AML treatment.
Subsequent experiments showed that targeting one of the genes, KAT2A, can destroy AML cells without harming normal blood cells.
This research was published in Cell Reports.
For this study, the researchers used CRISPR-Cas9 gene-editing technology to screen leukemia cells for vulnerable points. The team said they refined the technology so they could disrupt all genes in the leukemia cell genome individually.
This allowed the researchers to identify those genes whose disruption was detrimental to the growth and survival of AML cells, particularly the AML cell lines MOLM-13, HL-60, OCI-AML2, OCI-AML3, and MV4-11.
“Previous studies showed proof of principle, but this is one of the first systematic attempts to identify the genetic vulnerabilities of AML,” said study author Kosuke Yusa, PhD, of Wellcome Trust Sanger Institute in Hinxton, Cambridge, UK.
“We have improved and applied CRISPR-Cas9 technology to look at what actually kills cells.”
In this way, the researchers identified 492 genes that are essential for AML cell survival, including 227 genes that are druggable.
The team noted that a handful of the genes they identified—including DOT1L, BCL2, and MEN1—are already established therapeutic targets, but most of them are not.
The researchers chose to perform additional experiments with one of the genes they identified, KAT2A, to demonstrate the validity of their findings.
KAT2A was one of 66 genes that were essential to 3 or more of the AML cell lines studied. KAT2A was essential for survival in MOLM-13, OCI-AML2, and OCI-AML3.
The team inhibited KAT2A in vitro using genetic and drug-based techniques. Results showed that disrupting KAT2A inhibited the growth and survival of AML cells but did not affect normal blood cells.
“This is an exciting finding, as KAT2A inhibition worked on a number of primary AML cells with diverse genotypes,” said study author Konstantinos Tzelepis, a PhD student at Wellcome Trust Sanger Institute.
“Whilst the gene needs to be studied in greater depth to understand its potential for use in the clinic, we show that targeting KAT2A destroyed AML cells in the laboratory while sparing healthy blood cells.”
The researchers also targeted KAT2A in transgenic mice. The team observed a significant reduction in AML cell expansion and a significant improvement in survival when KAT2A was disrupted.
“This research has led to the identification of many potential gene targets for future AML therapy, which we are making available to other researchers to explore,” said study author George Vassiliou, PhD, of Wellcome Trust Sanger Institute.
“Whilst KAT2A inhibition now needs to be investigated as a treatment strategy for acute myeloid leukemia, there are many more candidates to pursue by the leukemia research community. Our hope is that this work will lead to more effective treatments against AML that will improve both the survival and the quality of life of patients.”
By adapting CRISPR-Cas9 technology and using it to screen the leukemia genome, researchers have identified hundreds of potential therapeutic targets for acute myeloid leukemia (AML).
The group’s work revealed nearly 500 genes, many of which had not been identified previously, that might serve as targets for AML treatment.
Subsequent experiments showed that targeting one of the genes, KAT2A, can destroy AML cells without harming normal blood cells.
This research was published in Cell Reports.
For this study, the researchers used CRISPR-Cas9 gene-editing technology to screen leukemia cells for vulnerable points. The team said they refined the technology so they could disrupt all genes in the leukemia cell genome individually.
This allowed the researchers to identify those genes whose disruption was detrimental to the growth and survival of AML cells, particularly the AML cell lines MOLM-13, HL-60, OCI-AML2, OCI-AML3, and MV4-11.
“Previous studies showed proof of principle, but this is one of the first systematic attempts to identify the genetic vulnerabilities of AML,” said study author Kosuke Yusa, PhD, of Wellcome Trust Sanger Institute in Hinxton, Cambridge, UK.
“We have improved and applied CRISPR-Cas9 technology to look at what actually kills cells.”
In this way, the researchers identified 492 genes that are essential for AML cell survival, including 227 genes that are druggable.
The team noted that a handful of the genes they identified—including DOT1L, BCL2, and MEN1—are already established therapeutic targets, but most of them are not.
The researchers chose to perform additional experiments with one of the genes they identified, KAT2A, to demonstrate the validity of their findings.
KAT2A was one of 66 genes that were essential to 3 or more of the AML cell lines studied. KAT2A was essential for survival in MOLM-13, OCI-AML2, and OCI-AML3.
The team inhibited KAT2A in vitro using genetic and drug-based techniques. Results showed that disrupting KAT2A inhibited the growth and survival of AML cells but did not affect normal blood cells.
“This is an exciting finding, as KAT2A inhibition worked on a number of primary AML cells with diverse genotypes,” said study author Konstantinos Tzelepis, a PhD student at Wellcome Trust Sanger Institute.
“Whilst the gene needs to be studied in greater depth to understand its potential for use in the clinic, we show that targeting KAT2A destroyed AML cells in the laboratory while sparing healthy blood cells.”
The researchers also targeted KAT2A in transgenic mice. The team observed a significant reduction in AML cell expansion and a significant improvement in survival when KAT2A was disrupted.
“This research has led to the identification of many potential gene targets for future AML therapy, which we are making available to other researchers to explore,” said study author George Vassiliou, PhD, of Wellcome Trust Sanger Institute.
“Whilst KAT2A inhibition now needs to be investigated as a treatment strategy for acute myeloid leukemia, there are many more candidates to pursue by the leukemia research community. Our hope is that this work will lead to more effective treatments against AML that will improve both the survival and the quality of life of patients.”
New nanoparticles may improve chemo delivery
Image from PNAS
A new type of nanoparticle can deliver chemotherapy directly and efficiently to individual cells, according to research published in the Journal of the American Chemical Society.
These nanoparticles, known as connectosomes, are equipped with gap junctions—a pathway that allows for the rapid movement of molecules between 2 cells.
The gap junctions allow the connectosomes to create a direct channel to deliver drugs to each individual cell.
“Gap junctions are the cells’ mechanism for sharing small molecules between neighboring cells,” said study author Jeanne Stachowiak, PhD, of The University of Texas at Austin.
“We believed that there must be a way to utilize them for better drug delivery. The big challenge was in making the materials efficiently and showing that the drugs are delivered through the gap junctions and not some other component.”
To create the connectosomes, the researchers used a chemical process to derive liposomes from donor cells that were engineered to over-produce gap junctions, which are made of proteins.
The team then loaded the connectosomes with the chemotherapy drug doxorubicin.
In in vitro tests with human cells, the researchers found that doxorubicin delivered through connectosomes was 10 times as efficient at killing cancer cells as freely delivered doxorubicin.
Connectosomes were also 100 to 100,000 times as efficient as conventional nanoparticles in delivering doxorubicin, because a drug can diffuse more efficiently through a gap junction than across the oily lipid membrane.
“Connectosomes could open doors for the improved utilization of nanoparticles to deliver other types of therapies,” said Avinash Gadok, a doctoral student at The University of Texas at Austin.
“A huge advantage of nanoparticles is that they can target cells, which helps protect off-target tissues.”
Now, the researchers are investigating whether connectosomes can biochemically target tumor cells and whether they could be useful in inhibiting the migration of tumor cells.
Gap junctions are known to suppress cell migration, creating the potential for connectosomes to help control the movement of tumor cells out of the tumor and into the bloodstream.
“We would like to see whether this approach could delay metastasis while treating the tumor,” Dr Stachowiak said.
“It would be nice to have a multi-pronged approach where you have a particle that slows down metastasis, rapidly delivers drugs, and turns off expression of genes that are promoting the migration of tumor cells.”
Image from PNAS
A new type of nanoparticle can deliver chemotherapy directly and efficiently to individual cells, according to research published in the Journal of the American Chemical Society.
These nanoparticles, known as connectosomes, are equipped with gap junctions—a pathway that allows for the rapid movement of molecules between 2 cells.
The gap junctions allow the connectosomes to create a direct channel to deliver drugs to each individual cell.
“Gap junctions are the cells’ mechanism for sharing small molecules between neighboring cells,” said study author Jeanne Stachowiak, PhD, of The University of Texas at Austin.
“We believed that there must be a way to utilize them for better drug delivery. The big challenge was in making the materials efficiently and showing that the drugs are delivered through the gap junctions and not some other component.”
To create the connectosomes, the researchers used a chemical process to derive liposomes from donor cells that were engineered to over-produce gap junctions, which are made of proteins.
The team then loaded the connectosomes with the chemotherapy drug doxorubicin.
In in vitro tests with human cells, the researchers found that doxorubicin delivered through connectosomes was 10 times as efficient at killing cancer cells as freely delivered doxorubicin.
Connectosomes were also 100 to 100,000 times as efficient as conventional nanoparticles in delivering doxorubicin, because a drug can diffuse more efficiently through a gap junction than across the oily lipid membrane.
“Connectosomes could open doors for the improved utilization of nanoparticles to deliver other types of therapies,” said Avinash Gadok, a doctoral student at The University of Texas at Austin.
“A huge advantage of nanoparticles is that they can target cells, which helps protect off-target tissues.”
Now, the researchers are investigating whether connectosomes can biochemically target tumor cells and whether they could be useful in inhibiting the migration of tumor cells.
Gap junctions are known to suppress cell migration, creating the potential for connectosomes to help control the movement of tumor cells out of the tumor and into the bloodstream.
“We would like to see whether this approach could delay metastasis while treating the tumor,” Dr Stachowiak said.
“It would be nice to have a multi-pronged approach where you have a particle that slows down metastasis, rapidly delivers drugs, and turns off expression of genes that are promoting the migration of tumor cells.”
Image from PNAS
A new type of nanoparticle can deliver chemotherapy directly and efficiently to individual cells, according to research published in the Journal of the American Chemical Society.
These nanoparticles, known as connectosomes, are equipped with gap junctions—a pathway that allows for the rapid movement of molecules between 2 cells.
The gap junctions allow the connectosomes to create a direct channel to deliver drugs to each individual cell.
“Gap junctions are the cells’ mechanism for sharing small molecules between neighboring cells,” said study author Jeanne Stachowiak, PhD, of The University of Texas at Austin.
“We believed that there must be a way to utilize them for better drug delivery. The big challenge was in making the materials efficiently and showing that the drugs are delivered through the gap junctions and not some other component.”
To create the connectosomes, the researchers used a chemical process to derive liposomes from donor cells that were engineered to over-produce gap junctions, which are made of proteins.
The team then loaded the connectosomes with the chemotherapy drug doxorubicin.
In in vitro tests with human cells, the researchers found that doxorubicin delivered through connectosomes was 10 times as efficient at killing cancer cells as freely delivered doxorubicin.
Connectosomes were also 100 to 100,000 times as efficient as conventional nanoparticles in delivering doxorubicin, because a drug can diffuse more efficiently through a gap junction than across the oily lipid membrane.
“Connectosomes could open doors for the improved utilization of nanoparticles to deliver other types of therapies,” said Avinash Gadok, a doctoral student at The University of Texas at Austin.
“A huge advantage of nanoparticles is that they can target cells, which helps protect off-target tissues.”
Now, the researchers are investigating whether connectosomes can biochemically target tumor cells and whether they could be useful in inhibiting the migration of tumor cells.
Gap junctions are known to suppress cell migration, creating the potential for connectosomes to help control the movement of tumor cells out of the tumor and into the bloodstream.
“We would like to see whether this approach could delay metastasis while treating the tumor,” Dr Stachowiak said.
“It would be nice to have a multi-pronged approach where you have a particle that slows down metastasis, rapidly delivers drugs, and turns off expression of genes that are promoting the migration of tumor cells.”
New Initiative Expands Native Research Opportunities
IHS has announced that it is funding a new project: the National Native Health Research Training Initiative, a cooperative agreement aimed at building capacity, reducing health disparities, and sharing best practices in American Indian and Alaska Native (AI/AN) health research. The funding offers about $225,000 per year for up to 5 years.
Related: IHS Awards Funding for Health Care Self-Governance
The project is designed to promote tribally driven research through education and training opportunities. The initiative “will help expand the community of American Indian and Alaska Native researchers and enhance the ability of tribes to participate in and initiate research projects that address specific needs in their communities,” said IHS Principal Deputy Director Mary Smith.
The funding opportunity is open to a national membership organization of American Indian and Alaska Native scientists, researchers, and students. The organization selected will further the IHS research program objectives with expanded outreach and education efforts for AI/AN students, faculty, and health professionals by, for example, making it easier for tribes to use research findings to address AI/AN needs or by promoting health research methods to better understand the effects of traditional Indian medicine, indigenous knowledge, and traditional ecological knowledge on AI/AN health.
Related: IHS and CMS Partner for Patient Safety Improvements
IHS says it also expects the award recipient to develop regular conference training for health professionals and tribal leaders about health research methods, findings, and best practices to meet the needs and advance the health and health care of AI/AN people.
IHS has announced that it is funding a new project: the National Native Health Research Training Initiative, a cooperative agreement aimed at building capacity, reducing health disparities, and sharing best practices in American Indian and Alaska Native (AI/AN) health research. The funding offers about $225,000 per year for up to 5 years.
Related: IHS Awards Funding for Health Care Self-Governance
The project is designed to promote tribally driven research through education and training opportunities. The initiative “will help expand the community of American Indian and Alaska Native researchers and enhance the ability of tribes to participate in and initiate research projects that address specific needs in their communities,” said IHS Principal Deputy Director Mary Smith.
The funding opportunity is open to a national membership organization of American Indian and Alaska Native scientists, researchers, and students. The organization selected will further the IHS research program objectives with expanded outreach and education efforts for AI/AN students, faculty, and health professionals by, for example, making it easier for tribes to use research findings to address AI/AN needs or by promoting health research methods to better understand the effects of traditional Indian medicine, indigenous knowledge, and traditional ecological knowledge on AI/AN health.
Related: IHS and CMS Partner for Patient Safety Improvements
IHS says it also expects the award recipient to develop regular conference training for health professionals and tribal leaders about health research methods, findings, and best practices to meet the needs and advance the health and health care of AI/AN people.
IHS has announced that it is funding a new project: the National Native Health Research Training Initiative, a cooperative agreement aimed at building capacity, reducing health disparities, and sharing best practices in American Indian and Alaska Native (AI/AN) health research. The funding offers about $225,000 per year for up to 5 years.
Related: IHS Awards Funding for Health Care Self-Governance
The project is designed to promote tribally driven research through education and training opportunities. The initiative “will help expand the community of American Indian and Alaska Native researchers and enhance the ability of tribes to participate in and initiate research projects that address specific needs in their communities,” said IHS Principal Deputy Director Mary Smith.
The funding opportunity is open to a national membership organization of American Indian and Alaska Native scientists, researchers, and students. The organization selected will further the IHS research program objectives with expanded outreach and education efforts for AI/AN students, faculty, and health professionals by, for example, making it easier for tribes to use research findings to address AI/AN needs or by promoting health research methods to better understand the effects of traditional Indian medicine, indigenous knowledge, and traditional ecological knowledge on AI/AN health.
Related: IHS and CMS Partner for Patient Safety Improvements
IHS says it also expects the award recipient to develop regular conference training for health professionals and tribal leaders about health research methods, findings, and best practices to meet the needs and advance the health and health care of AI/AN people.
Non-Invasive Testing for CAD
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Secukinumab for psoriasis at 4 years: undiminished efficacy and safety
VIENNA – Four-year follow-up of patients on secukinumab for psoriasis shows sustained very high efficacy, with almost 100% of patients who had a Psoriasis Area and Severity Index (PASI) 90 or 100 response at 1 year maintaining it through 4 years, Robert Bissonnette, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
“I must warn you that my presentation will be very boring as compared to what I’ve seen earlier at this meeting, the very cutting edge phase II and phase III data being presented. My presentation doesn’t contain any surprises. However, as a clinician who is using interleukin-17A inhibition in my practice to treat psoriasis patients, that’s probably what I want,” said Dr. Bissonnette, president of Innovaderm Research in Montreal.
“This is the longest-term safety and efficacy data available to date for patients treated with an IL-17 antagonist using an approved dose,” he noted.
Dr. Bissonnette presented 4-year results in the 165 participants who took the approved regimen from the start of the study. These were patients at the serious end of the disease severity spectrum. Their mean baseline PASI score was 23.5, with 33% of their body surface area being affected. Their mean Dermatology Life Quality Index (DLQI) score was 13.1. The mean body mass index was 28.7 kg/m2. A total of 71% of subjects had previously been on systemic therapy. One-third of participants had been on other biologics.
At 1 year, 88.9% of subjects had a PASI 75 response; at 4 years, the PASI 75 rate was 88.5%. Similarly, the PASI 90 rate was 68.5% at 1 year and 66.4% after 4 years. The PASI 100 rate was 43.8% at 1 year and 43.5% at year 4.
After 1 year on secukinumab, patients showed a mean 91.1% improvement, compared with their baseline PASI score. At 4 years, the figure was 90.8%.
Bearing in mind that the average baseline DLQI score at baseline was 13.1, it’s noteworthy that after 1 year on secukinumab, 72.7% of patients had a DLQI of 0 or 1, indicating psoriasis had no impact on their life. At year 4, the rate was 70.8%, Dr. Bissonnette continued.
As an audience member observed, however, the study population decreased from 165 patients to 131 over the course of 4 years. And since this was an “as observed” analysis, outcomes were counted only in those patients still in the study. It’s accepted as a legitimate statistical method, but it casts outcomes in a particularly favorable light.
“The main reason for dropouts was for personal reasons,” Dr. Bissonnette explained in response. “Number two was lack of or loss of efficacy. Loss of efficacy over time occurred at an absolute rate of 4%-8% per year.”
Overall, adverse event rates declined over the course of 4 years of follow-up.
“This is reassuring, but I don’t think it’s evidence that adverse events actually decrease over time because of longer use of secukinumab. I think it’s probably due to something we usually see in long-term clinical trials: a phenomenon of underreporting. When patients are treated with a new agent they tend to be very, very conscientious about what’s going on with their well-being. They will report a slight sore throat, a slight congestion. But once they’ve been on treatment for a longer time they’re less likely to report those very minor adverse events,” according to the dermatologist.
The Food and Drug Administration requires clinical trialists to keep careful track of selected adverse events in studies of biologic agents. In 4 years on secukinumab, there were no cases of tuberculosis, neutropenia, major adverse cardiovascular events, or Crohn’s disease. There were two cases of ulcerative colitis in year 2; however, one involved an exacerbation of preexisting disease. Also, two patients developed cancer other than nonmelanoma skin cancer in year 2. The incidence of vulvovaginal candidiasis was 1.8% during years 1 and 2, 0.6% in year 3, and zero in year 4.
Thus, the safety profile was favorable, with no pattern of increasing adverse events with longer medication use, Dr. Bissonnette concluded.
The study was sponsored by Novartis. Dr. Bissonnette reported serving as an investigator for and consultant to Novartis and 16 other pharmaceutical companies.
VIENNA – Four-year follow-up of patients on secukinumab for psoriasis shows sustained very high efficacy, with almost 100% of patients who had a Psoriasis Area and Severity Index (PASI) 90 or 100 response at 1 year maintaining it through 4 years, Robert Bissonnette, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
“I must warn you that my presentation will be very boring as compared to what I’ve seen earlier at this meeting, the very cutting edge phase II and phase III data being presented. My presentation doesn’t contain any surprises. However, as a clinician who is using interleukin-17A inhibition in my practice to treat psoriasis patients, that’s probably what I want,” said Dr. Bissonnette, president of Innovaderm Research in Montreal.
“This is the longest-term safety and efficacy data available to date for patients treated with an IL-17 antagonist using an approved dose,” he noted.
Dr. Bissonnette presented 4-year results in the 165 participants who took the approved regimen from the start of the study. These were patients at the serious end of the disease severity spectrum. Their mean baseline PASI score was 23.5, with 33% of their body surface area being affected. Their mean Dermatology Life Quality Index (DLQI) score was 13.1. The mean body mass index was 28.7 kg/m2. A total of 71% of subjects had previously been on systemic therapy. One-third of participants had been on other biologics.
At 1 year, 88.9% of subjects had a PASI 75 response; at 4 years, the PASI 75 rate was 88.5%. Similarly, the PASI 90 rate was 68.5% at 1 year and 66.4% after 4 years. The PASI 100 rate was 43.8% at 1 year and 43.5% at year 4.
After 1 year on secukinumab, patients showed a mean 91.1% improvement, compared with their baseline PASI score. At 4 years, the figure was 90.8%.
Bearing in mind that the average baseline DLQI score at baseline was 13.1, it’s noteworthy that after 1 year on secukinumab, 72.7% of patients had a DLQI of 0 or 1, indicating psoriasis had no impact on their life. At year 4, the rate was 70.8%, Dr. Bissonnette continued.
As an audience member observed, however, the study population decreased from 165 patients to 131 over the course of 4 years. And since this was an “as observed” analysis, outcomes were counted only in those patients still in the study. It’s accepted as a legitimate statistical method, but it casts outcomes in a particularly favorable light.
“The main reason for dropouts was for personal reasons,” Dr. Bissonnette explained in response. “Number two was lack of or loss of efficacy. Loss of efficacy over time occurred at an absolute rate of 4%-8% per year.”
Overall, adverse event rates declined over the course of 4 years of follow-up.
“This is reassuring, but I don’t think it’s evidence that adverse events actually decrease over time because of longer use of secukinumab. I think it’s probably due to something we usually see in long-term clinical trials: a phenomenon of underreporting. When patients are treated with a new agent they tend to be very, very conscientious about what’s going on with their well-being. They will report a slight sore throat, a slight congestion. But once they’ve been on treatment for a longer time they’re less likely to report those very minor adverse events,” according to the dermatologist.
The Food and Drug Administration requires clinical trialists to keep careful track of selected adverse events in studies of biologic agents. In 4 years on secukinumab, there were no cases of tuberculosis, neutropenia, major adverse cardiovascular events, or Crohn’s disease. There were two cases of ulcerative colitis in year 2; however, one involved an exacerbation of preexisting disease. Also, two patients developed cancer other than nonmelanoma skin cancer in year 2. The incidence of vulvovaginal candidiasis was 1.8% during years 1 and 2, 0.6% in year 3, and zero in year 4.
Thus, the safety profile was favorable, with no pattern of increasing adverse events with longer medication use, Dr. Bissonnette concluded.
The study was sponsored by Novartis. Dr. Bissonnette reported serving as an investigator for and consultant to Novartis and 16 other pharmaceutical companies.
VIENNA – Four-year follow-up of patients on secukinumab for psoriasis shows sustained very high efficacy, with almost 100% of patients who had a Psoriasis Area and Severity Index (PASI) 90 or 100 response at 1 year maintaining it through 4 years, Robert Bissonnette, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
“I must warn you that my presentation will be very boring as compared to what I’ve seen earlier at this meeting, the very cutting edge phase II and phase III data being presented. My presentation doesn’t contain any surprises. However, as a clinician who is using interleukin-17A inhibition in my practice to treat psoriasis patients, that’s probably what I want,” said Dr. Bissonnette, president of Innovaderm Research in Montreal.
“This is the longest-term safety and efficacy data available to date for patients treated with an IL-17 antagonist using an approved dose,” he noted.
Dr. Bissonnette presented 4-year results in the 165 participants who took the approved regimen from the start of the study. These were patients at the serious end of the disease severity spectrum. Their mean baseline PASI score was 23.5, with 33% of their body surface area being affected. Their mean Dermatology Life Quality Index (DLQI) score was 13.1. The mean body mass index was 28.7 kg/m2. A total of 71% of subjects had previously been on systemic therapy. One-third of participants had been on other biologics.
At 1 year, 88.9% of subjects had a PASI 75 response; at 4 years, the PASI 75 rate was 88.5%. Similarly, the PASI 90 rate was 68.5% at 1 year and 66.4% after 4 years. The PASI 100 rate was 43.8% at 1 year and 43.5% at year 4.
After 1 year on secukinumab, patients showed a mean 91.1% improvement, compared with their baseline PASI score. At 4 years, the figure was 90.8%.
Bearing in mind that the average baseline DLQI score at baseline was 13.1, it’s noteworthy that after 1 year on secukinumab, 72.7% of patients had a DLQI of 0 or 1, indicating psoriasis had no impact on their life. At year 4, the rate was 70.8%, Dr. Bissonnette continued.
As an audience member observed, however, the study population decreased from 165 patients to 131 over the course of 4 years. And since this was an “as observed” analysis, outcomes were counted only in those patients still in the study. It’s accepted as a legitimate statistical method, but it casts outcomes in a particularly favorable light.
“The main reason for dropouts was for personal reasons,” Dr. Bissonnette explained in response. “Number two was lack of or loss of efficacy. Loss of efficacy over time occurred at an absolute rate of 4%-8% per year.”
Overall, adverse event rates declined over the course of 4 years of follow-up.
“This is reassuring, but I don’t think it’s evidence that adverse events actually decrease over time because of longer use of secukinumab. I think it’s probably due to something we usually see in long-term clinical trials: a phenomenon of underreporting. When patients are treated with a new agent they tend to be very, very conscientious about what’s going on with their well-being. They will report a slight sore throat, a slight congestion. But once they’ve been on treatment for a longer time they’re less likely to report those very minor adverse events,” according to the dermatologist.
The Food and Drug Administration requires clinical trialists to keep careful track of selected adverse events in studies of biologic agents. In 4 years on secukinumab, there were no cases of tuberculosis, neutropenia, major adverse cardiovascular events, or Crohn’s disease. There were two cases of ulcerative colitis in year 2; however, one involved an exacerbation of preexisting disease. Also, two patients developed cancer other than nonmelanoma skin cancer in year 2. The incidence of vulvovaginal candidiasis was 1.8% during years 1 and 2, 0.6% in year 3, and zero in year 4.
Thus, the safety profile was favorable, with no pattern of increasing adverse events with longer medication use, Dr. Bissonnette concluded.
The study was sponsored by Novartis. Dr. Bissonnette reported serving as an investigator for and consultant to Novartis and 16 other pharmaceutical companies.
AT THE EADV CONGRESS
Key clinical point:
Major finding: After 1 year on secukinumab, 43.8% of psoriasis patients had a PASI 100 response. After 3 additional years on the interleukin-17A inhibitor, the rate was virtually unchanged at 43.5%.
Data source: This was analysis of 165 psoriasis patients on secukinumab at the approved dose prospectively followed for 4 years in an extension of a phase III clinical trial.
Disclosures: Novartis sponsored the study. The presenter reported serving as an investigator for and consultant to Novartis and 16 other pharmaceutical companies.
Unvaccinated patients rack up billions in preventable costs
Adult patients who avoid vaccines cost the health care system $7 billion in preventable illness in 2015, according to a meta-analysis.
Sachiko Ozawa, PhD., of the University of North Carolina at Chapel Hill and her colleagues estimated the annual economic burden of diseases associated with 10 adult vaccines recommended by the Centers for Disease Control and Prevention that protect against 14 pathogens by looking at studies with U.S. cost data for adult age groups and using cost-of-illness modeling (Health Affairs 2016 Oct. doi:10.1377/hlthaff.2016.0462).
The cost of outpatient care ranged between $108 and $457 per patient, while the cost of medication ranged from $0 per patient for diseases that do not have curative drug treatments to $605 per patients treated for tetanus, investigators found. When it came to inpatient care, costs ranged from $5,770 per patient for those hospitalized for influenza to $15,600 for those hospitalized for invasive meningococcal disease.
Outpatient productivity loss per patient ranged from $29 for patients requiring a single outpatient visit to $154 for patients diagnosed with HPV-related cancers. Inpatient productivity loss per person ranged from $122 for patients with mumps to $580 for patients with tetanus.
The results underscore the need for improved uptake of vaccines among adults and the need for patients to better appreciate the value of vaccines, Dr. Ozawa said in an interview.
“If these individuals were to be vaccinated, than $7 billion in costs would be eliminated every year from the U.S. economy,” she said. “That’s pretty big. That’s the high-level takeaway.”
Dr. Ozawa said that she hopes the study will spur some creative policy solutions to increase vaccine usage, while preserving the autonomy of patients to make more informed choices.
[email protected]
On Twitter @legal_med
Adult patients who avoid vaccines cost the health care system $7 billion in preventable illness in 2015, according to a meta-analysis.
Sachiko Ozawa, PhD., of the University of North Carolina at Chapel Hill and her colleagues estimated the annual economic burden of diseases associated with 10 adult vaccines recommended by the Centers for Disease Control and Prevention that protect against 14 pathogens by looking at studies with U.S. cost data for adult age groups and using cost-of-illness modeling (Health Affairs 2016 Oct. doi:10.1377/hlthaff.2016.0462).
The cost of outpatient care ranged between $108 and $457 per patient, while the cost of medication ranged from $0 per patient for diseases that do not have curative drug treatments to $605 per patients treated for tetanus, investigators found. When it came to inpatient care, costs ranged from $5,770 per patient for those hospitalized for influenza to $15,600 for those hospitalized for invasive meningococcal disease.
Outpatient productivity loss per patient ranged from $29 for patients requiring a single outpatient visit to $154 for patients diagnosed with HPV-related cancers. Inpatient productivity loss per person ranged from $122 for patients with mumps to $580 for patients with tetanus.
The results underscore the need for improved uptake of vaccines among adults and the need for patients to better appreciate the value of vaccines, Dr. Ozawa said in an interview.
“If these individuals were to be vaccinated, than $7 billion in costs would be eliminated every year from the U.S. economy,” she said. “That’s pretty big. That’s the high-level takeaway.”
Dr. Ozawa said that she hopes the study will spur some creative policy solutions to increase vaccine usage, while preserving the autonomy of patients to make more informed choices.
[email protected]
On Twitter @legal_med
Adult patients who avoid vaccines cost the health care system $7 billion in preventable illness in 2015, according to a meta-analysis.
Sachiko Ozawa, PhD., of the University of North Carolina at Chapel Hill and her colleagues estimated the annual economic burden of diseases associated with 10 adult vaccines recommended by the Centers for Disease Control and Prevention that protect against 14 pathogens by looking at studies with U.S. cost data for adult age groups and using cost-of-illness modeling (Health Affairs 2016 Oct. doi:10.1377/hlthaff.2016.0462).
The cost of outpatient care ranged between $108 and $457 per patient, while the cost of medication ranged from $0 per patient for diseases that do not have curative drug treatments to $605 per patients treated for tetanus, investigators found. When it came to inpatient care, costs ranged from $5,770 per patient for those hospitalized for influenza to $15,600 for those hospitalized for invasive meningococcal disease.
Outpatient productivity loss per patient ranged from $29 for patients requiring a single outpatient visit to $154 for patients diagnosed with HPV-related cancers. Inpatient productivity loss per person ranged from $122 for patients with mumps to $580 for patients with tetanus.
The results underscore the need for improved uptake of vaccines among adults and the need for patients to better appreciate the value of vaccines, Dr. Ozawa said in an interview.
“If these individuals were to be vaccinated, than $7 billion in costs would be eliminated every year from the U.S. economy,” she said. “That’s pretty big. That’s the high-level takeaway.”
Dr. Ozawa said that she hopes the study will spur some creative policy solutions to increase vaccine usage, while preserving the autonomy of patients to make more informed choices.
[email protected]
On Twitter @legal_med
Pyuria is an important tool in diagnosing UTI in infants
Diagnosing urinary tract infections can be achieved by determining the white blood cell concentration of the patient’s urine, according to a new study.
“Previously recommended pyuria thresholds for the presumptive diagnosis of UTI in young infants were based on manual microscopy of centrifuged urine [but] test performance has not been studied in newer automated systems that analyze uncentrifuged urine,” wrote Pradip P. Chaudhari, MD, and his associates at Harvard University in Boston.
Of these 2,700 infants with a median age of 1.7 months, 211 (7.8%) had a urine culture come back positive for UTI. Likelihood ratio (LR) positive and negative were calculated to determine the microscopic pyuria thresholds at which UTIs became more likely in both dilute and concentrated urine. A white blood cell to high-power field (WBC/HPF) count of 3 yielded an LR-positive of 9.9 and LR-negative of just 0.15, making it the cutoff for dilute urine samples. For concentrated urine samples, 6 WBC/HPF had an LR-positive of 10.1 and LR-negative of 0.17, making it the cutoff for those samples. Leukocyte esterase (LE) thresholds also were determined for dipstick testing, with investigators finding that any positive result on the dipstick was a strong indicator of UTI.
“The optimal diagnostic threshold for microscopic pyuria varies by urine concentration,” the authors concluded. “For young infants, urine concentration should be incorporated into the interpretation of uncentrifuged urine analyzed by automated microscopic urinalysis systems.”
There was no external funding for this study. Dr. Chaudhari and his coauthors did not report any relevant financial disclosures.
In this issue of Pediatrics, Chaudhari et al. share the results of a study of the impact of urine concentration on the optimal threshold in the new era of automated urinalysis. Centrifugation of urine specimens has long been standard laboratory practice, presumably performed to concentrate sediment and facilitate the detection of cellular elements and bacteria.
However, for the many sites that do not have machines for automated urinalyses (virtually all office practices, for example), the most important finding in this study may well be how well LE [leukocyte esterase] performs regardless of urine concentration. The optimal threshold for LE is not clear, however. The authors use “small” as their threshold for LE. At any threshold, can a negative urinalysis be relied on to exclude the diagnosis of UTI? A “positive” culture without inflammation evident in the urine is likely due to contamination, very early infection (rare), or asymptomatic bacteriuria (positive urine cultures in febrile children can still represent asymptomatic bacteriuria, because the fever may be due to a source other than the urinary tract).
If there are, in fact, some true UTIs without evidence of inflammation from the urinalysis, are they as harmful as those with “pyuria”?
Animal data demonstrate it is the inflammatory response, not the presence of organisms, that causes renal damage in the form of scarring. So the role of using evidence of inflammation in the urine to screen for who needs a culture seems justified on the basis not only of practicality at point of care and likelihood of UTI, but also sparing individuals at low to no risk of scarring from invasive urine collection. Moreover, using the urinalysis as a screen permits selecting individuals for antimicrobial treatment 24 hours sooner than if clinicians were to wait for culture results before treating. The urinalysis provides a practical window for clinicians to render prompt treatment. And Chaudhari et al. provide valuable assistance for interpreting the results of automated urinalyses.
Kenneth B. Roberts, MD , is a professor of therapeutic radiology at Yale University, New Haven, Conn. He did not report any relevant financial disclosures. These comments are excerpted from a commentary that accompanied Dr. Chaudhari and his associates’ study ( Pediatrics. 2016;138(5):e20162877 ).
In this issue of Pediatrics, Chaudhari et al. share the results of a study of the impact of urine concentration on the optimal threshold in the new era of automated urinalysis. Centrifugation of urine specimens has long been standard laboratory practice, presumably performed to concentrate sediment and facilitate the detection of cellular elements and bacteria.
However, for the many sites that do not have machines for automated urinalyses (virtually all office practices, for example), the most important finding in this study may well be how well LE [leukocyte esterase] performs regardless of urine concentration. The optimal threshold for LE is not clear, however. The authors use “small” as their threshold for LE. At any threshold, can a negative urinalysis be relied on to exclude the diagnosis of UTI? A “positive” culture without inflammation evident in the urine is likely due to contamination, very early infection (rare), or asymptomatic bacteriuria (positive urine cultures in febrile children can still represent asymptomatic bacteriuria, because the fever may be due to a source other than the urinary tract).
If there are, in fact, some true UTIs without evidence of inflammation from the urinalysis, are they as harmful as those with “pyuria”?
Animal data demonstrate it is the inflammatory response, not the presence of organisms, that causes renal damage in the form of scarring. So the role of using evidence of inflammation in the urine to screen for who needs a culture seems justified on the basis not only of practicality at point of care and likelihood of UTI, but also sparing individuals at low to no risk of scarring from invasive urine collection. Moreover, using the urinalysis as a screen permits selecting individuals for antimicrobial treatment 24 hours sooner than if clinicians were to wait for culture results before treating. The urinalysis provides a practical window for clinicians to render prompt treatment. And Chaudhari et al. provide valuable assistance for interpreting the results of automated urinalyses.
Kenneth B. Roberts, MD , is a professor of therapeutic radiology at Yale University, New Haven, Conn. He did not report any relevant financial disclosures. These comments are excerpted from a commentary that accompanied Dr. Chaudhari and his associates’ study ( Pediatrics. 2016;138(5):e20162877 ).
In this issue of Pediatrics, Chaudhari et al. share the results of a study of the impact of urine concentration on the optimal threshold in the new era of automated urinalysis. Centrifugation of urine specimens has long been standard laboratory practice, presumably performed to concentrate sediment and facilitate the detection of cellular elements and bacteria.
However, for the many sites that do not have machines for automated urinalyses (virtually all office practices, for example), the most important finding in this study may well be how well LE [leukocyte esterase] performs regardless of urine concentration. The optimal threshold for LE is not clear, however. The authors use “small” as their threshold for LE. At any threshold, can a negative urinalysis be relied on to exclude the diagnosis of UTI? A “positive” culture without inflammation evident in the urine is likely due to contamination, very early infection (rare), or asymptomatic bacteriuria (positive urine cultures in febrile children can still represent asymptomatic bacteriuria, because the fever may be due to a source other than the urinary tract).
If there are, in fact, some true UTIs without evidence of inflammation from the urinalysis, are they as harmful as those with “pyuria”?
Animal data demonstrate it is the inflammatory response, not the presence of organisms, that causes renal damage in the form of scarring. So the role of using evidence of inflammation in the urine to screen for who needs a culture seems justified on the basis not only of practicality at point of care and likelihood of UTI, but also sparing individuals at low to no risk of scarring from invasive urine collection. Moreover, using the urinalysis as a screen permits selecting individuals for antimicrobial treatment 24 hours sooner than if clinicians were to wait for culture results before treating. The urinalysis provides a practical window for clinicians to render prompt treatment. And Chaudhari et al. provide valuable assistance for interpreting the results of automated urinalyses.
Kenneth B. Roberts, MD , is a professor of therapeutic radiology at Yale University, New Haven, Conn. He did not report any relevant financial disclosures. These comments are excerpted from a commentary that accompanied Dr. Chaudhari and his associates’ study ( Pediatrics. 2016;138(5):e20162877 ).
Diagnosing urinary tract infections can be achieved by determining the white blood cell concentration of the patient’s urine, according to a new study.
“Previously recommended pyuria thresholds for the presumptive diagnosis of UTI in young infants were based on manual microscopy of centrifuged urine [but] test performance has not been studied in newer automated systems that analyze uncentrifuged urine,” wrote Pradip P. Chaudhari, MD, and his associates at Harvard University in Boston.
Of these 2,700 infants with a median age of 1.7 months, 211 (7.8%) had a urine culture come back positive for UTI. Likelihood ratio (LR) positive and negative were calculated to determine the microscopic pyuria thresholds at which UTIs became more likely in both dilute and concentrated urine. A white blood cell to high-power field (WBC/HPF) count of 3 yielded an LR-positive of 9.9 and LR-negative of just 0.15, making it the cutoff for dilute urine samples. For concentrated urine samples, 6 WBC/HPF had an LR-positive of 10.1 and LR-negative of 0.17, making it the cutoff for those samples. Leukocyte esterase (LE) thresholds also were determined for dipstick testing, with investigators finding that any positive result on the dipstick was a strong indicator of UTI.
“The optimal diagnostic threshold for microscopic pyuria varies by urine concentration,” the authors concluded. “For young infants, urine concentration should be incorporated into the interpretation of uncentrifuged urine analyzed by automated microscopic urinalysis systems.”
There was no external funding for this study. Dr. Chaudhari and his coauthors did not report any relevant financial disclosures.
Diagnosing urinary tract infections can be achieved by determining the white blood cell concentration of the patient’s urine, according to a new study.
“Previously recommended pyuria thresholds for the presumptive diagnosis of UTI in young infants were based on manual microscopy of centrifuged urine [but] test performance has not been studied in newer automated systems that analyze uncentrifuged urine,” wrote Pradip P. Chaudhari, MD, and his associates at Harvard University in Boston.
Of these 2,700 infants with a median age of 1.7 months, 211 (7.8%) had a urine culture come back positive for UTI. Likelihood ratio (LR) positive and negative were calculated to determine the microscopic pyuria thresholds at which UTIs became more likely in both dilute and concentrated urine. A white blood cell to high-power field (WBC/HPF) count of 3 yielded an LR-positive of 9.9 and LR-negative of just 0.15, making it the cutoff for dilute urine samples. For concentrated urine samples, 6 WBC/HPF had an LR-positive of 10.1 and LR-negative of 0.17, making it the cutoff for those samples. Leukocyte esterase (LE) thresholds also were determined for dipstick testing, with investigators finding that any positive result on the dipstick was a strong indicator of UTI.
“The optimal diagnostic threshold for microscopic pyuria varies by urine concentration,” the authors concluded. “For young infants, urine concentration should be incorporated into the interpretation of uncentrifuged urine analyzed by automated microscopic urinalysis systems.”
There was no external funding for this study. Dr. Chaudhari and his coauthors did not report any relevant financial disclosures.
FROM PEDIATRICS
Key clinical point:
Major finding: UTIs can be safely diagnosed if the patient has a pyuria threshold of at least 3 WBC/HPF in dilute urine and 6 WBC/HPF in concentrated urine.
Data source: Retrospective cross-sectional study of 2,700 infants younger than 3 months between May 2009 and December 2014.
Disclosures: No external funding for this study; authors did not report any relevant financial disclosures.
Treatment of depression – nonpharmacologic vs. pharmacologic
Major depressive disorder (MDD) affects 16% of adults in the United States at some point in their lives. It is one of the most important causes of disability, time off from work, and personal distress, accounting for more than 8 million office visits per year.
Recent information shows that while 8% of the population screens positive for depression, only a quarter of those with depression receive treatment. Most patients with depression are cared for by primary care physicians, not psychiatrists.1 It is important that primary care physicians are familiar with the range of evidence-based treatments for depression and their relative efficacy. Most patients with depression receive antidepressant medication and less than one-third of patients receive some form of psychotherapy.1 The American College of Physicians guideline reviews the evidence regarding the relative efficacy and safety of second-generation antidepressants and nonpharmacologic treatment of depression.2
Outcomes evaluated in this guideline include response, remission, functional capacity, quality of life, reduction of suicidality or hospitalizations, and harms.
The pharmacotherapy treatment of depression, as assessed in this guideline, are second-generation antidepressants (SGAs), which include selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and selective serotonin norepinephrine reuptake inhibitors. Previous reviews have shown that the SGAs have similar efficacy and safety with the side effects varying among the different medications; common side effects include constipation, diarrhea, nausea, decreased sexual ability, dizziness, headache, insomnia, and fatigue.
The strongest evidence, rated as moderate quality, comes from trials comparing SGAs to a form of psychotherapy called cognitive-behavioral therapy (CBT). CBT uses the technique of “collaborative empiricism” to question patients maladaptive beliefs, and by examining those beliefs, help patients to take on interpretations of reality that are less biased by their initial negative thoughts. Through these “cognitive” exercises, patients begin to take on healthier, more-adaptive approaches to the social, physical, and emotional challenges in their lives. These interpretations are then “tested” in the real world, the behavioral aspect of CBT. Studies that ranged in time from 8 to 52 weeks in patients with MDD showed SGAs and CBT to have equal efficacy with regard to response and remission of depression to therapy. Combining SGA and CBT, compared with SGA alone, did not show a difference in outcomes of response to therapy or remission of depression, though patients who received both therapies had some improved efficacy in work function.
When SGAs were compared with interpersonal therapy, psychodynamic therapy, St. John’s wort, acupuncture, and exercise, there was low-quality evidence that these interventions performed with equal efficacy to SGAs. Two trials of exercise, compared with sertraline, had moderate-quality evidence showing similar efficacy between the two treatments.
When patients have an incomplete response to initial treatment with an SGA, there was no difference in response or remission when using a strategy of switching from one SGA to another versus switching to cognitive therapy. Similarly, with regard to augmentation, CBT appears to work equally to augmenting initial SGA therapy with bupropion or buspirone.
The guidelines discuss that, with regard to adverse effects, while the discontinuation rates of SGAs and CBT are similar, CBT likely has fewer side effects. In addition, it is important to recognize that CBT has lower relapse rate associated with its use than do SGAs. This is presumably because once a skill set is developed when learning CBT, those skills can continue to be used long term.
The bottom line
Most patients who experience depression are cared for by their primary care physician. Treatments for depression include psychotherapy, complementary and alternative medicine (CAM), exercise, and pharmacotherapy. After discussion with the patient, the American College of Physicians recommends choosing either cognitive-behavioral therapy or second-generation antidepressants when treating depression.
References
1. Olfson M, Blanco C, Marcus SC. Treatment of Adult Depression in the United States. JAMA Intern Med. 2016 Oct;176(10):1482-91.
2. Qaseem A, et al. Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016 Mar 1;164:350-59.
Dr. Skolnik is associate director of the family medicine residency program at Abington (Pa.) Memorial Hospital and professor of family and community medicine at Temple University in Philadelphia. Aaron Sutton is a behavioral therapy consultant in the family medicine residency program at Abington Memorial Hospital.
Major depressive disorder (MDD) affects 16% of adults in the United States at some point in their lives. It is one of the most important causes of disability, time off from work, and personal distress, accounting for more than 8 million office visits per year.
Recent information shows that while 8% of the population screens positive for depression, only a quarter of those with depression receive treatment. Most patients with depression are cared for by primary care physicians, not psychiatrists.1 It is important that primary care physicians are familiar with the range of evidence-based treatments for depression and their relative efficacy. Most patients with depression receive antidepressant medication and less than one-third of patients receive some form of psychotherapy.1 The American College of Physicians guideline reviews the evidence regarding the relative efficacy and safety of second-generation antidepressants and nonpharmacologic treatment of depression.2
Outcomes evaluated in this guideline include response, remission, functional capacity, quality of life, reduction of suicidality or hospitalizations, and harms.
The pharmacotherapy treatment of depression, as assessed in this guideline, are second-generation antidepressants (SGAs), which include selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and selective serotonin norepinephrine reuptake inhibitors. Previous reviews have shown that the SGAs have similar efficacy and safety with the side effects varying among the different medications; common side effects include constipation, diarrhea, nausea, decreased sexual ability, dizziness, headache, insomnia, and fatigue.
The strongest evidence, rated as moderate quality, comes from trials comparing SGAs to a form of psychotherapy called cognitive-behavioral therapy (CBT). CBT uses the technique of “collaborative empiricism” to question patients maladaptive beliefs, and by examining those beliefs, help patients to take on interpretations of reality that are less biased by their initial negative thoughts. Through these “cognitive” exercises, patients begin to take on healthier, more-adaptive approaches to the social, physical, and emotional challenges in their lives. These interpretations are then “tested” in the real world, the behavioral aspect of CBT. Studies that ranged in time from 8 to 52 weeks in patients with MDD showed SGAs and CBT to have equal efficacy with regard to response and remission of depression to therapy. Combining SGA and CBT, compared with SGA alone, did not show a difference in outcomes of response to therapy or remission of depression, though patients who received both therapies had some improved efficacy in work function.
When SGAs were compared with interpersonal therapy, psychodynamic therapy, St. John’s wort, acupuncture, and exercise, there was low-quality evidence that these interventions performed with equal efficacy to SGAs. Two trials of exercise, compared with sertraline, had moderate-quality evidence showing similar efficacy between the two treatments.
When patients have an incomplete response to initial treatment with an SGA, there was no difference in response or remission when using a strategy of switching from one SGA to another versus switching to cognitive therapy. Similarly, with regard to augmentation, CBT appears to work equally to augmenting initial SGA therapy with bupropion or buspirone.
The guidelines discuss that, with regard to adverse effects, while the discontinuation rates of SGAs and CBT are similar, CBT likely has fewer side effects. In addition, it is important to recognize that CBT has lower relapse rate associated with its use than do SGAs. This is presumably because once a skill set is developed when learning CBT, those skills can continue to be used long term.
The bottom line
Most patients who experience depression are cared for by their primary care physician. Treatments for depression include psychotherapy, complementary and alternative medicine (CAM), exercise, and pharmacotherapy. After discussion with the patient, the American College of Physicians recommends choosing either cognitive-behavioral therapy or second-generation antidepressants when treating depression.
References
1. Olfson M, Blanco C, Marcus SC. Treatment of Adult Depression in the United States. JAMA Intern Med. 2016 Oct;176(10):1482-91.
2. Qaseem A, et al. Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016 Mar 1;164:350-59.
Dr. Skolnik is associate director of the family medicine residency program at Abington (Pa.) Memorial Hospital and professor of family and community medicine at Temple University in Philadelphia. Aaron Sutton is a behavioral therapy consultant in the family medicine residency program at Abington Memorial Hospital.
Major depressive disorder (MDD) affects 16% of adults in the United States at some point in their lives. It is one of the most important causes of disability, time off from work, and personal distress, accounting for more than 8 million office visits per year.
Recent information shows that while 8% of the population screens positive for depression, only a quarter of those with depression receive treatment. Most patients with depression are cared for by primary care physicians, not psychiatrists.1 It is important that primary care physicians are familiar with the range of evidence-based treatments for depression and their relative efficacy. Most patients with depression receive antidepressant medication and less than one-third of patients receive some form of psychotherapy.1 The American College of Physicians guideline reviews the evidence regarding the relative efficacy and safety of second-generation antidepressants and nonpharmacologic treatment of depression.2
Outcomes evaluated in this guideline include response, remission, functional capacity, quality of life, reduction of suicidality or hospitalizations, and harms.
The pharmacotherapy treatment of depression, as assessed in this guideline, are second-generation antidepressants (SGAs), which include selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and selective serotonin norepinephrine reuptake inhibitors. Previous reviews have shown that the SGAs have similar efficacy and safety with the side effects varying among the different medications; common side effects include constipation, diarrhea, nausea, decreased sexual ability, dizziness, headache, insomnia, and fatigue.
The strongest evidence, rated as moderate quality, comes from trials comparing SGAs to a form of psychotherapy called cognitive-behavioral therapy (CBT). CBT uses the technique of “collaborative empiricism” to question patients maladaptive beliefs, and by examining those beliefs, help patients to take on interpretations of reality that are less biased by their initial negative thoughts. Through these “cognitive” exercises, patients begin to take on healthier, more-adaptive approaches to the social, physical, and emotional challenges in their lives. These interpretations are then “tested” in the real world, the behavioral aspect of CBT. Studies that ranged in time from 8 to 52 weeks in patients with MDD showed SGAs and CBT to have equal efficacy with regard to response and remission of depression to therapy. Combining SGA and CBT, compared with SGA alone, did not show a difference in outcomes of response to therapy or remission of depression, though patients who received both therapies had some improved efficacy in work function.
When SGAs were compared with interpersonal therapy, psychodynamic therapy, St. John’s wort, acupuncture, and exercise, there was low-quality evidence that these interventions performed with equal efficacy to SGAs. Two trials of exercise, compared with sertraline, had moderate-quality evidence showing similar efficacy between the two treatments.
When patients have an incomplete response to initial treatment with an SGA, there was no difference in response or remission when using a strategy of switching from one SGA to another versus switching to cognitive therapy. Similarly, with regard to augmentation, CBT appears to work equally to augmenting initial SGA therapy with bupropion or buspirone.
The guidelines discuss that, with regard to adverse effects, while the discontinuation rates of SGAs and CBT are similar, CBT likely has fewer side effects. In addition, it is important to recognize that CBT has lower relapse rate associated with its use than do SGAs. This is presumably because once a skill set is developed when learning CBT, those skills can continue to be used long term.
The bottom line
Most patients who experience depression are cared for by their primary care physician. Treatments for depression include psychotherapy, complementary and alternative medicine (CAM), exercise, and pharmacotherapy. After discussion with the patient, the American College of Physicians recommends choosing either cognitive-behavioral therapy or second-generation antidepressants when treating depression.
References
1. Olfson M, Blanco C, Marcus SC. Treatment of Adult Depression in the United States. JAMA Intern Med. 2016 Oct;176(10):1482-91.
2. Qaseem A, et al. Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016 Mar 1;164:350-59.
Dr. Skolnik is associate director of the family medicine residency program at Abington (Pa.) Memorial Hospital and professor of family and community medicine at Temple University in Philadelphia. Aaron Sutton is a behavioral therapy consultant in the family medicine residency program at Abington Memorial Hospital.