Women with platinum-sensitive recurrent ovarian cancer who received maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor had no significant decreases in health-related quality of life, outcomes data from two randomized clinical trials show.

Health-related quality of life (HRQOL) analyses from the SOLO2/ENGOT-Ov-21 trial comparing olaparib (Lynparza) with placebo and the ENGOT-OV16/NOVA trial comparing niraparib (Zejula) with placebo as maintenance therapy in women with ongoing responses to their last platinum-based chemotherapy showed that neither agent had major detrimental effects on patient-reported outcomes, further supporting the progression-free survival benefits previously seen with each agent in its respective trials.

“These results show the significant benefit of maintenance olaparib to patients beyond the RECIST [Response Evaluation Criteria in Solid Tumors] definition of progression, the primary endpoint of SOLO2, and highlight the importance of including patient-centered outcomes in addition to HRQOL in trials of maintenance therapy, in line with the recommendations of the 5th Ovarian Cancer Consensus Conference,” wrote Michael Friedlander, MD, of the University of New South Wales Clinical School and Prince of Wales Hospital in Randwick, New South Wales, Australia, and his colleagues.

Similarly, Amit M. Oza, MD, of Princess Margaret Cancer Centre in Toronto, and his coinvestigators in the ENGOT-OV16/NOVA trial found that “niraparib has no significant negative effect on QOL in patients with recurrent ovarian cancer. Combined with the evidence of increased progression-free survival with niraparib in the maintenance setting, these findings support the addition of niraparib as a component of standard of care.”

Both studies were published online in The Lancet Oncology: Friedlander M et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30343-7, and Oza AM et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30333-4.

SOLO2 QOL summary

In SOLO2, patients with a germline BRCA1 or BRCA2 mutation and platinum-sensitive ovarian cancer that relapsed after at least two lines of chemotherapy were randomly assigned to receive either oral olaparib 300 mg twice daily (196 patients) or placebo (99 patients).

The prespecified primary HRQOL analysis looked at the change from baseline in the Functional Assessment of Cancer Therapy–Ovarian Cancer (FACT-O) Trial Outcome Index (TOI) score during the first 12 months of the study.

In addition, the investigators examined secondary planned QOL analyses, including duration of good quality of life, defined as time without significant symptoms of toxicity, or TWiST, and quality-adjusted progression-free survival (QAPFS).

The adjusted average mean change from baseline over the first 12 months in TOI was –2.90 with olaparib vs. –2.87 with placebo (nonsignificant).

In contrast, patients treated with olaparib had significantly better mean QAPFS (13.96 vs. 7.28 months) and TWiST (15.03 vs. 7.70 months) results.

“All these predefined endpoints support the benefit to patients of a prolongation of progression-free survival, which is the primary endpoint in maintenance trials in ovarian cancer, and should be routinely included in future trials,” wrote Dr. Friedlander and his associates.
 

ENGOT-OV16/NOVA QOL summary

Investigators for this trial enrolled patients into two independent cohorts based on germline BRCA mutations or lack thereof. In all, 138 patients were assigned to niraparib and 65 to placebo in the germline BRCA mutation cohort, and 234 to niraparib and 116 to placebo in the nonmutation cohort.

The current study assessed patient-reported outcomes in the intention-to-treat population using different validated instruments from those assessed in SOLO2: the Functional Assessment of Cancer Therapy–Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L).

The outcomes were reported every 8 weeks for the first 14 treatment cycles and every 12 weeks thereafter.

The investigators looked at the effects of hematologic toxicities on QOL with disutility analyses (measuring the decrement on QOL of a particular symptom or complication) of the most common grade 3-4 adverse events (thrombocytopenia, anemia, and neutropenia) using a mixed model with covariates.

They found that overall QOL scores remained stable during treatment and the preprogression period among patients on niraparib in each cohort, and that there were no significant differences in preprogression EQ-5D-5L scores between niraparib- or placebo-treated patients in either cohort.

In addition, patient-reported lack of energy and pain, two of the most common baseline symptoms, either remained stable or improved during maintenance, although the proportion of patients reporting nausea increased at cycle 2. The incidence of nausea declined over subsequent cycles, and eventually approached baseline levels, the investigators said.

Hematologic toxicities were the most common grade 3 or 4 adverse events seen in patients treated with niraparib, including thrombocytopenia in 34%, anemia in 25%, and neutropenia in 20%. However, disutility analyses showed no significant effects of these toxicities on QOL measures.

“This analysis did not examine integrated measures of duration and QOL such as time without symptoms and toxicity or quality-adjusted progression-free survival. Although these analyses were beyond the scope of this report, these measures are potentially of interest and we plan to assess these as part of future research,” wrote Dr. Oza and his associates.

SOURCE: Friedlander M et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30343-7. Oza AM et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30333-4.

Women with platinum-sensitive recurrent ovarian cancer who received maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor had no significant decreases in health-related quality of life, outcomes data from two randomized clinical trials show.

Health-related quality of life (HRQOL) analyses from the SOLO2/ENGOT-Ov-21 trial comparing olaparib (Lynparza) with placebo and the ENGOT-OV16/NOVA trial comparing niraparib (Zejula) with placebo as maintenance therapy in women with ongoing responses to their last platinum-based chemotherapy showed that neither agent had major detrimental effects on patient-reported outcomes, further supporting the progression-free survival benefits previously seen with each agent in its respective trials.

“These results show the significant benefit of maintenance olaparib to patients beyond the RECIST [Response Evaluation Criteria in Solid Tumors] definition of progression, the primary endpoint of SOLO2, and highlight the importance of including patient-centered outcomes in addition to HRQOL in trials of maintenance therapy, in line with the recommendations of the 5th Ovarian Cancer Consensus Conference,” wrote Michael Friedlander, MD, of the University of New South Wales Clinical School and Prince of Wales Hospital in Randwick, New South Wales, Australia, and his colleagues.

Similarly, Amit M. Oza, MD, of Princess Margaret Cancer Centre in Toronto, and his coinvestigators in the ENGOT-OV16/NOVA trial found that “niraparib has no significant negative effect on QOL in patients with recurrent ovarian cancer. Combined with the evidence of increased progression-free survival with niraparib in the maintenance setting, these findings support the addition of niraparib as a component of standard of care.”

Both studies were published online in The Lancet Oncology: Friedlander M et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30343-7, and Oza AM et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30333-4.

SOLO2 QOL summary

In SOLO2, patients with a germline BRCA1 or BRCA2 mutation and platinum-sensitive ovarian cancer that relapsed after at least two lines of chemotherapy were randomly assigned to receive either oral olaparib 300 mg twice daily (196 patients) or placebo (99 patients).

The prespecified primary HRQOL analysis looked at the change from baseline in the Functional Assessment of Cancer Therapy–Ovarian Cancer (FACT-O) Trial Outcome Index (TOI) score during the first 12 months of the study.

In addition, the investigators examined secondary planned QOL analyses, including duration of good quality of life, defined as time without significant symptoms of toxicity, or TWiST, and quality-adjusted progression-free survival (QAPFS).

The adjusted average mean change from baseline over the first 12 months in TOI was –2.90 with olaparib vs. –2.87 with placebo (nonsignificant).

In contrast, patients treated with olaparib had significantly better mean QAPFS (13.96 vs. 7.28 months) and TWiST (15.03 vs. 7.70 months) results.

“All these predefined endpoints support the benefit to patients of a prolongation of progression-free survival, which is the primary endpoint in maintenance trials in ovarian cancer, and should be routinely included in future trials,” wrote Dr. Friedlander and his associates.
 

ENGOT-OV16/NOVA QOL summary

Investigators for this trial enrolled patients into two independent cohorts based on germline BRCA mutations or lack thereof. In all, 138 patients were assigned to niraparib and 65 to placebo in the germline BRCA mutation cohort, and 234 to niraparib and 116 to placebo in the nonmutation cohort.

The current study assessed patient-reported outcomes in the intention-to-treat population using different validated instruments from those assessed in SOLO2: the Functional Assessment of Cancer Therapy–Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L).

The outcomes were reported every 8 weeks for the first 14 treatment cycles and every 12 weeks thereafter.

The investigators looked at the effects of hematologic toxicities on QOL with disutility analyses (measuring the decrement on QOL of a particular symptom or complication) of the most common grade 3-4 adverse events (thrombocytopenia, anemia, and neutropenia) using a mixed model with covariates.

They found that overall QOL scores remained stable during treatment and the preprogression period among patients on niraparib in each cohort, and that there were no significant differences in preprogression EQ-5D-5L scores between niraparib- or placebo-treated patients in either cohort.

In addition, patient-reported lack of energy and pain, two of the most common baseline symptoms, either remained stable or improved during maintenance, although the proportion of patients reporting nausea increased at cycle 2. The incidence of nausea declined over subsequent cycles, and eventually approached baseline levels, the investigators said.

Hematologic toxicities were the most common grade 3 or 4 adverse events seen in patients treated with niraparib, including thrombocytopenia in 34%, anemia in 25%, and neutropenia in 20%. However, disutility analyses showed no significant effects of these toxicities on QOL measures.

“This analysis did not examine integrated measures of duration and QOL such as time without symptoms and toxicity or quality-adjusted progression-free survival. Although these analyses were beyond the scope of this report, these measures are potentially of interest and we plan to assess these as part of future research,” wrote Dr. Oza and his associates.

SOURCE: Friedlander M et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30343-7. Oza AM et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30333-4.

Women with platinum-sensitive recurrent ovarian cancer who received maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor had no significant decreases in health-related quality of life, outcomes data from two randomized clinical trials show.

Health-related quality of life (HRQOL) analyses from the SOLO2/ENGOT-Ov-21 trial comparing olaparib (Lynparza) with placebo and the ENGOT-OV16/NOVA trial comparing niraparib (Zejula) with placebo as maintenance therapy in women with ongoing responses to their last platinum-based chemotherapy showed that neither agent had major detrimental effects on patient-reported outcomes, further supporting the progression-free survival benefits previously seen with each agent in its respective trials.

“These results show the significant benefit of maintenance olaparib to patients beyond the RECIST [Response Evaluation Criteria in Solid Tumors] definition of progression, the primary endpoint of SOLO2, and highlight the importance of including patient-centered outcomes in addition to HRQOL in trials of maintenance therapy, in line with the recommendations of the 5th Ovarian Cancer Consensus Conference,” wrote Michael Friedlander, MD, of the University of New South Wales Clinical School and Prince of Wales Hospital in Randwick, New South Wales, Australia, and his colleagues.

Similarly, Amit M. Oza, MD, of Princess Margaret Cancer Centre in Toronto, and his coinvestigators in the ENGOT-OV16/NOVA trial found that “niraparib has no significant negative effect on QOL in patients with recurrent ovarian cancer. Combined with the evidence of increased progression-free survival with niraparib in the maintenance setting, these findings support the addition of niraparib as a component of standard of care.”

Both studies were published online in The Lancet Oncology: Friedlander M et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30343-7, and Oza AM et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30333-4.

SOLO2 QOL summary

In SOLO2, patients with a germline BRCA1 or BRCA2 mutation and platinum-sensitive ovarian cancer that relapsed after at least two lines of chemotherapy were randomly assigned to receive either oral olaparib 300 mg twice daily (196 patients) or placebo (99 patients).

The prespecified primary HRQOL analysis looked at the change from baseline in the Functional Assessment of Cancer Therapy–Ovarian Cancer (FACT-O) Trial Outcome Index (TOI) score during the first 12 months of the study.

In addition, the investigators examined secondary planned QOL analyses, including duration of good quality of life, defined as time without significant symptoms of toxicity, or TWiST, and quality-adjusted progression-free survival (QAPFS).

The adjusted average mean change from baseline over the first 12 months in TOI was –2.90 with olaparib vs. –2.87 with placebo (nonsignificant).

In contrast, patients treated with olaparib had significantly better mean QAPFS (13.96 vs. 7.28 months) and TWiST (15.03 vs. 7.70 months) results.

“All these predefined endpoints support the benefit to patients of a prolongation of progression-free survival, which is the primary endpoint in maintenance trials in ovarian cancer, and should be routinely included in future trials,” wrote Dr. Friedlander and his associates.
 

ENGOT-OV16/NOVA QOL summary

Investigators for this trial enrolled patients into two independent cohorts based on germline BRCA mutations or lack thereof. In all, 138 patients were assigned to niraparib and 65 to placebo in the germline BRCA mutation cohort, and 234 to niraparib and 116 to placebo in the nonmutation cohort.

The current study assessed patient-reported outcomes in the intention-to-treat population using different validated instruments from those assessed in SOLO2: the Functional Assessment of Cancer Therapy–Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L).

The outcomes were reported every 8 weeks for the first 14 treatment cycles and every 12 weeks thereafter.

The investigators looked at the effects of hematologic toxicities on QOL with disutility analyses (measuring the decrement on QOL of a particular symptom or complication) of the most common grade 3-4 adverse events (thrombocytopenia, anemia, and neutropenia) using a mixed model with covariates.

They found that overall QOL scores remained stable during treatment and the preprogression period among patients on niraparib in each cohort, and that there were no significant differences in preprogression EQ-5D-5L scores between niraparib- or placebo-treated patients in either cohort.

In addition, patient-reported lack of energy and pain, two of the most common baseline symptoms, either remained stable or improved during maintenance, although the proportion of patients reporting nausea increased at cycle 2. The incidence of nausea declined over subsequent cycles, and eventually approached baseline levels, the investigators said.

Hematologic toxicities were the most common grade 3 or 4 adverse events seen in patients treated with niraparib, including thrombocytopenia in 34%, anemia in 25%, and neutropenia in 20%. However, disutility analyses showed no significant effects of these toxicities on QOL measures.

“This analysis did not examine integrated measures of duration and QOL such as time without symptoms and toxicity or quality-adjusted progression-free survival. Although these analyses were beyond the scope of this report, these measures are potentially of interest and we plan to assess these as part of future research,” wrote Dr. Oza and his associates.

SOURCE: Friedlander M et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30343-7. Oza AM et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30333-4.

Evidence-based recommendations for appropriate nephrology testing in children are the latest installment of the American Board of Internal Medicine Foundation’s “Choosing Wisely” campaign.

[email protected]

Evidence-based recommendations for appropriate nephrology testing in children are the latest installment of the American Board of Internal Medicine Foundation’s “Choosing Wisely” campaign.

[email protected]

Evidence-based recommendations for appropriate nephrology testing in children are the latest installment of the American Board of Internal Medicine Foundation’s “Choosing Wisely” campaign.

[email protected]

In 2012, a study conducted by Zullig and colleagues revealed that about 40,000 cancer cases are reported annually to the Veterans Affairs Central Cancer Registry.¹ This represented about 3% of all cancer cases in the US. Within the VA patient population, the most commonly diagnosed cancers are prostate, lung and bronchial, colorectal, urinary and bladder cancers, and skin melanomas. This mirrors the commonly diagnosed cancers within the total US patient population.

Click here to continue reading.

In 2012, a study conducted by Zullig and colleagues revealed that about 40,000 cancer cases are reported annually to the Veterans Affairs Central Cancer Registry.¹ This represented about 3% of all cancer cases in the US. Within the VA patient population, the most commonly diagnosed cancers are prostate, lung and bronchial, colorectal, urinary and bladder cancers, and skin melanomas. This mirrors the commonly diagnosed cancers within the total US patient population.

Click here to continue reading.

In 2012, a study conducted by Zullig and colleagues revealed that about 40,000 cancer cases are reported annually to the Veterans Affairs Central Cancer Registry.¹ This represented about 3% of all cancer cases in the US. Within the VA patient population, the most commonly diagnosed cancers are prostate, lung and bronchial, colorectal, urinary and bladder cancers, and skin melanomas. This mirrors the commonly diagnosed cancers within the total US patient population.

Click here to continue reading.

What’s the best way to encourage patients to get screened for HIV? Money is a time-honored effective incentive, but researchers from University of California say the default option may be even better. They conducted, to their knowledge, the first head-to-head study of 2 types of behavioral economics interventions (cash incentives vs opt-out) in any health behavior context. The working hypothesis was based on “nudge theory,” a concept in behavioral science, political theory, and economics that says using positive reinforcement and indirect suggestions can influence behavior and decision making.

In the study, patients aged 13 to 64 years were told the emergency department was offering rapid screening HIV tests, with results available within 2 hours. Then each patient was given a test offer: opt-in (“You can let me, your nurse, or your doctor know if you’d like a test today”); active choice (“Would you like a test today?”); or opt-out (“You will be tested unless you decline.”) Patients assigned to a positive monetary incentive were told “To encourage testing today we are offering a $1 (or $5 or $10) cash incentive.”

Of 8,715 patients, 4,831 (55%) accepted an HIV test. Those offered no monetary incentive accepted 52% of test offers. The $1 offer did not increase test acceptance, but the $5 and $10 offers increased acceptance rates by 10.5 and 15 percentage points, respectively. Active-choice increased acceptance by 11.5 percentage points compared with that of opt-in offers.

However, opt-out testing—essentially a default option—had the largest effect, increasing acceptance by 24 percentage points. The next most effective was the $10 incentive.

The researchers say the effects were consistent across all levels of patient risk of infection, although the effects were somewhat attenuated when defaults and incentives were used together. In general, higher risk patients tested at higher rates than did lower risk patients.

Defaults have been “understudied in medicine,” the researchers say. The study not only reaffirms that behavioral economics “nudges” work, but also that “small interventions can have significant effects.” Moreover, the finding that moving from opt-in to opt-out testing influenced behavior more than even the largest incentive reinforces the notion that “medicine is not just a transaction, and what we say to patients matters.”

Source:
Montoy JCC, Dow WH, Kaplan BC. PLoS One. 2018;13(7):e0199833.
doi: 10.1371/journal.pone.0199833.

What’s the best way to encourage patients to get screened for HIV? Money is a time-honored effective incentive, but researchers from University of California say the default option may be even better. They conducted, to their knowledge, the first head-to-head study of 2 types of behavioral economics interventions (cash incentives vs opt-out) in any health behavior context. The working hypothesis was based on “nudge theory,” a concept in behavioral science, political theory, and economics that says using positive reinforcement and indirect suggestions can influence behavior and decision making.

In the study, patients aged 13 to 64 years were told the emergency department was offering rapid screening HIV tests, with results available within 2 hours. Then each patient was given a test offer: opt-in (“You can let me, your nurse, or your doctor know if you’d like a test today”); active choice (“Would you like a test today?”); or opt-out (“You will be tested unless you decline.”) Patients assigned to a positive monetary incentive were told “To encourage testing today we are offering a $1 (or $5 or $10) cash incentive.”

Of 8,715 patients, 4,831 (55%) accepted an HIV test. Those offered no monetary incentive accepted 52% of test offers. The $1 offer did not increase test acceptance, but the $5 and $10 offers increased acceptance rates by 10.5 and 15 percentage points, respectively. Active-choice increased acceptance by 11.5 percentage points compared with that of opt-in offers.

However, opt-out testing—essentially a default option—had the largest effect, increasing acceptance by 24 percentage points. The next most effective was the $10 incentive.

The researchers say the effects were consistent across all levels of patient risk of infection, although the effects were somewhat attenuated when defaults and incentives were used together. In general, higher risk patients tested at higher rates than did lower risk patients.

Defaults have been “understudied in medicine,” the researchers say. The study not only reaffirms that behavioral economics “nudges” work, but also that “small interventions can have significant effects.” Moreover, the finding that moving from opt-in to opt-out testing influenced behavior more than even the largest incentive reinforces the notion that “medicine is not just a transaction, and what we say to patients matters.”

Source:
Montoy JCC, Dow WH, Kaplan BC. PLoS One. 2018;13(7):e0199833.
doi: 10.1371/journal.pone.0199833.

What’s the best way to encourage patients to get screened for HIV? Money is a time-honored effective incentive, but researchers from University of California say the default option may be even better. They conducted, to their knowledge, the first head-to-head study of 2 types of behavioral economics interventions (cash incentives vs opt-out) in any health behavior context. The working hypothesis was based on “nudge theory,” a concept in behavioral science, political theory, and economics that says using positive reinforcement and indirect suggestions can influence behavior and decision making.

In the study, patients aged 13 to 64 years were told the emergency department was offering rapid screening HIV tests, with results available within 2 hours. Then each patient was given a test offer: opt-in (“You can let me, your nurse, or your doctor know if you’d like a test today”); active choice (“Would you like a test today?”); or opt-out (“You will be tested unless you decline.”) Patients assigned to a positive monetary incentive were told “To encourage testing today we are offering a $1 (or $5 or $10) cash incentive.”

Of 8,715 patients, 4,831 (55%) accepted an HIV test. Those offered no monetary incentive accepted 52% of test offers. The $1 offer did not increase test acceptance, but the $5 and $10 offers increased acceptance rates by 10.5 and 15 percentage points, respectively. Active-choice increased acceptance by 11.5 percentage points compared with that of opt-in offers.

However, opt-out testing—essentially a default option—had the largest effect, increasing acceptance by 24 percentage points. The next most effective was the $10 incentive.

The researchers say the effects were consistent across all levels of patient risk of infection, although the effects were somewhat attenuated when defaults and incentives were used together. In general, higher risk patients tested at higher rates than did lower risk patients.

Defaults have been “understudied in medicine,” the researchers say. The study not only reaffirms that behavioral economics “nudges” work, but also that “small interventions can have significant effects.” Moreover, the finding that moving from opt-in to opt-out testing influenced behavior more than even the largest incentive reinforces the notion that “medicine is not just a transaction, and what we say to patients matters.”

Source:
Montoy JCC, Dow WH, Kaplan BC. PLoS One. 2018;13(7):e0199833.
doi: 10.1371/journal.pone.0199833.

Hospital of Philadelphia

A kinase called heme-regulated inhibitor (HRI) could be a therapeutic target for sickle cell disease (SCD) and some forms of β-thalassemia, according to researchers.

The team found that reducing the activity of HRI (also known as EIF2AK1) can boost the production of fetal hemoglobin (HbF).

Gerd Blobel MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania, and his colleagues reported this discovery in Science.

Dr Blobel noted that hydroxyurea remains the only approved drug that can increase fetal Hb in adults.

“Our goal was to identify new potential drug targets that regulate fetal Hb levels,” he said.

To that end, the researchers conducted a CRISPR-Cas9 screen targeting protein kinases. They designed a library of single-guide RNAs targeting 482 kinase domains, which covered almost all known kinases in the human genome.

The team attempted to determine if interference with any of the kinases in an immortalized human red blood cell line would increase HbF levels.

Results suggested that HRI, an erythroid-specific kinase that controls protein translation, is a repressor of HbF.

To confirm that HRI plays a key role in regulating HbF levels, the researchers depleted HRI in primary cultured human red blood cell precursors.

Reduced activity of HRI resulted in decreased phosphorylation of eIF2a and increased levels of HbF, but interfering with HRI levels did not impair cell viability or maturation.

The researchers next showed that HRI was a repressor of HbF in cultured primary cells from patients with SCD.

When HRI levels were artificially reduced, HbF levels were significantly increased, and cells were less prone to sickling. This suggested to the researchers that “HRI depletion may achieve therapeutically relevant levels of HbF.”

Mechanistically, the effects of HRI on HbF were shown to occur, in large measure, through modulating the activity of BCL11A, a direct repressor of HbF transcription.

The observation that HRI inhibition elevated HbF levels and reduced cell sickling in culture suggested that future pharmacologic HRI inhibitors might provide clinical benefit in patients with SCD.

To that end, an important aspect of this work was to determine if the effect of HRI inhibition could be increased with another drug added to the mix, Dr Blobel said.

He and his colleagues therefore tested whether pomalidomide, which was previously shown to increase HbF in an experimental setting, could be such a drug.

HRI depletion in combination with pomalidomide treatment raised HbF levels more than either treatment alone, suggesting that HRI inhibition might be combined with another HbF-inducing drug to increase the therapeutic index.

Hospital of Philadelphia

A kinase called heme-regulated inhibitor (HRI) could be a therapeutic target for sickle cell disease (SCD) and some forms of β-thalassemia, according to researchers.

The team found that reducing the activity of HRI (also known as EIF2AK1) can boost the production of fetal hemoglobin (HbF).

Gerd Blobel MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania, and his colleagues reported this discovery in Science.

Dr Blobel noted that hydroxyurea remains the only approved drug that can increase fetal Hb in adults.

“Our goal was to identify new potential drug targets that regulate fetal Hb levels,” he said.

To that end, the researchers conducted a CRISPR-Cas9 screen targeting protein kinases. They designed a library of single-guide RNAs targeting 482 kinase domains, which covered almost all known kinases in the human genome.

The team attempted to determine if interference with any of the kinases in an immortalized human red blood cell line would increase HbF levels.

Results suggested that HRI, an erythroid-specific kinase that controls protein translation, is a repressor of HbF.

To confirm that HRI plays a key role in regulating HbF levels, the researchers depleted HRI in primary cultured human red blood cell precursors.

Reduced activity of HRI resulted in decreased phosphorylation of eIF2a and increased levels of HbF, but interfering with HRI levels did not impair cell viability or maturation.

The researchers next showed that HRI was a repressor of HbF in cultured primary cells from patients with SCD.

When HRI levels were artificially reduced, HbF levels were significantly increased, and cells were less prone to sickling. This suggested to the researchers that “HRI depletion may achieve therapeutically relevant levels of HbF.”

Mechanistically, the effects of HRI on HbF were shown to occur, in large measure, through modulating the activity of BCL11A, a direct repressor of HbF transcription.

The observation that HRI inhibition elevated HbF levels and reduced cell sickling in culture suggested that future pharmacologic HRI inhibitors might provide clinical benefit in patients with SCD.

To that end, an important aspect of this work was to determine if the effect of HRI inhibition could be increased with another drug added to the mix, Dr Blobel said.

He and his colleagues therefore tested whether pomalidomide, which was previously shown to increase HbF in an experimental setting, could be such a drug.

HRI depletion in combination with pomalidomide treatment raised HbF levels more than either treatment alone, suggesting that HRI inhibition might be combined with another HbF-inducing drug to increase the therapeutic index.

Hospital of Philadelphia

A kinase called heme-regulated inhibitor (HRI) could be a therapeutic target for sickle cell disease (SCD) and some forms of β-thalassemia, according to researchers.

The team found that reducing the activity of HRI (also known as EIF2AK1) can boost the production of fetal hemoglobin (HbF).

Gerd Blobel MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania, and his colleagues reported this discovery in Science.

Dr Blobel noted that hydroxyurea remains the only approved drug that can increase fetal Hb in adults.

“Our goal was to identify new potential drug targets that regulate fetal Hb levels,” he said.

To that end, the researchers conducted a CRISPR-Cas9 screen targeting protein kinases. They designed a library of single-guide RNAs targeting 482 kinase domains, which covered almost all known kinases in the human genome.

The team attempted to determine if interference with any of the kinases in an immortalized human red blood cell line would increase HbF levels.

Results suggested that HRI, an erythroid-specific kinase that controls protein translation, is a repressor of HbF.

To confirm that HRI plays a key role in regulating HbF levels, the researchers depleted HRI in primary cultured human red blood cell precursors.

Reduced activity of HRI resulted in decreased phosphorylation of eIF2a and increased levels of HbF, but interfering with HRI levels did not impair cell viability or maturation.

The researchers next showed that HRI was a repressor of HbF in cultured primary cells from patients with SCD.

When HRI levels were artificially reduced, HbF levels were significantly increased, and cells were less prone to sickling. This suggested to the researchers that “HRI depletion may achieve therapeutically relevant levels of HbF.”

Mechanistically, the effects of HRI on HbF were shown to occur, in large measure, through modulating the activity of BCL11A, a direct repressor of HbF transcription.

The observation that HRI inhibition elevated HbF levels and reduced cell sickling in culture suggested that future pharmacologic HRI inhibitors might provide clinical benefit in patients with SCD.

To that end, an important aspect of this work was to determine if the effect of HRI inhibition could be increased with another drug added to the mix, Dr Blobel said.

He and his colleagues therefore tested whether pomalidomide, which was previously shown to increase HbF in an experimental setting, could be such a drug.

HRI depletion in combination with pomalidomide treatment raised HbF levels more than either treatment alone, suggesting that HRI inhibition might be combined with another HbF-inducing drug to increase the therapeutic index.

Photo by Rhoda Baer

A review of data from more than 19 million people indicates that diabetes significantly raises a person’s risk of developing cancer.

When researchers compared patients with diabetes and without, both male and female diabetics had an increased risk of leukemias and lymphomas as well as certain solid tumors.

Researchers also found that diabetes conferred a higher cancer risk for women than men, both for all cancers combined and for some specific cancers, including leukemia.

“The link between diabetes and the risk of developing cancer is now firmly established,” said Toshiaki Ohkuma, PhD, of The George Institute for Global Health at the University of New South Wales in Australia.

“We have also demonstrated, for the first time, that women with diabetes are more likely to develop any form of cancer and have a significantly higher chance of developing kidney, oral, and stomach cancers and leukemia.”

Dr Ohkuma and his colleagues reported these findings in Diabetologia.

The researchers conducted a systematic search in PubMed MEDLINE to identify reports on the links between diabetes and cancer. Additional reports were identified from the reference lists of the relevant studies.

Only those cohort studies providing relative risks (RRs) for the association between diabetes and cancer for both women and men were included. In total, 107 relevant articles were identified, along with 36 cohorts of individual participant data.

RRs for cancer were obtained for patients with diabetes (types 1 and 2 combined) versus those without diabetes, for both men and women. The women-to-men ratios of these relative risk ratios (RRRs) were then calculated to determine the excess risk in women if present.

Data on all-site cancer was available from 47 studies, involving 121 cohorts and 19,239,302 individuals.

Diabetics vs non-diabetics

Women with diabetes had a 27% higher risk of all-site cancer compared to women without diabetes (RR=1.27; 95% CI 1.21, 1.32; P<0.001).

For men, the risk of all-site cancer was 19% higher among those with diabetes than those without (RR=1.19; 95% CI 1.13, 1.25; P<0.001).

There were several hematologic malignancies for which diabetics had an increased risk, as shown in the following table.

Sex comparison

Calculation of the women-to-men ratio revealed that women with diabetes had a 6% greater excess risk of all-site cancer compared to men with diabetes (RRR=1.06; 95% CI 1.03, 1.09; P<0.001).

The women-to-men ratios also showed significantly higher risks for female diabetics for:

• Kidney cancer—RRR=1.11 (99% CI 1.04, 1.18; P<0.001)
• Oral cancer—RRR=1.13 (99% CI 1.00, 1.28; P=0.009)
• Stomach cancer—RRR=1.14 (99% CI 1.07, 1.22; P<0.001)
• Leukemia—RRR=1.15 (99% CI 1.02, 1.28; P=0.002).

However, women had a significantly lower risk of liver cancer (RRR=0.88; 99% CI 0.79, 0.99; P=0.005).

There are several possible reasons for the excess cancer risk observed in women, according to study author Sanne Peters, PhD, of The George Institute for Global Health at the University of Oxford in the UK.

For example, on average, women are in the pre-diabetic state of impaired glucose tolerance 2 years longer than men.

“Historically, we know that women are often under-treated when they first present with symptoms of diabetes, are less likely to receive intensive care, and are not taking the same levels of medications as men,” Dr Peters said. “All of these could go some way into explaining why women are at greater risk of developing cancer, but, without more research, we can’t be certain.”

Photo by Rhoda Baer

A review of data from more than 19 million people indicates that diabetes significantly raises a person’s risk of developing cancer.

When researchers compared patients with diabetes and without, both male and female diabetics had an increased risk of leukemias and lymphomas as well as certain solid tumors.

Researchers also found that diabetes conferred a higher cancer risk for women than men, both for all cancers combined and for some specific cancers, including leukemia.

“The link between diabetes and the risk of developing cancer is now firmly established,” said Toshiaki Ohkuma, PhD, of The George Institute for Global Health at the University of New South Wales in Australia.

“We have also demonstrated, for the first time, that women with diabetes are more likely to develop any form of cancer and have a significantly higher chance of developing kidney, oral, and stomach cancers and leukemia.”

Dr Ohkuma and his colleagues reported these findings in Diabetologia.

The researchers conducted a systematic search in PubMed MEDLINE to identify reports on the links between diabetes and cancer. Additional reports were identified from the reference lists of the relevant studies.

Only those cohort studies providing relative risks (RRs) for the association between diabetes and cancer for both women and men were included. In total, 107 relevant articles were identified, along with 36 cohorts of individual participant data.

RRs for cancer were obtained for patients with diabetes (types 1 and 2 combined) versus those without diabetes, for both men and women. The women-to-men ratios of these relative risk ratios (RRRs) were then calculated to determine the excess risk in women if present.

Data on all-site cancer was available from 47 studies, involving 121 cohorts and 19,239,302 individuals.

Diabetics vs non-diabetics

Women with diabetes had a 27% higher risk of all-site cancer compared to women without diabetes (RR=1.27; 95% CI 1.21, 1.32; P<0.001).

For men, the risk of all-site cancer was 19% higher among those with diabetes than those without (RR=1.19; 95% CI 1.13, 1.25; P<0.001).

There were several hematologic malignancies for which diabetics had an increased risk, as shown in the following table.

Sex comparison

Calculation of the women-to-men ratio revealed that women with diabetes had a 6% greater excess risk of all-site cancer compared to men with diabetes (RRR=1.06; 95% CI 1.03, 1.09; P<0.001).

The women-to-men ratios also showed significantly higher risks for female diabetics for:

• Kidney cancer—RRR=1.11 (99% CI 1.04, 1.18; P<0.001)
• Oral cancer—RRR=1.13 (99% CI 1.00, 1.28; P=0.009)
• Stomach cancer—RRR=1.14 (99% CI 1.07, 1.22; P<0.001)
• Leukemia—RRR=1.15 (99% CI 1.02, 1.28; P=0.002).

However, women had a significantly lower risk of liver cancer (RRR=0.88; 99% CI 0.79, 0.99; P=0.005).

There are several possible reasons for the excess cancer risk observed in women, according to study author Sanne Peters, PhD, of The George Institute for Global Health at the University of Oxford in the UK.

For example, on average, women are in the pre-diabetic state of impaired glucose tolerance 2 years longer than men.

“Historically, we know that women are often under-treated when they first present with symptoms of diabetes, are less likely to receive intensive care, and are not taking the same levels of medications as men,” Dr Peters said. “All of these could go some way into explaining why women are at greater risk of developing cancer, but, without more research, we can’t be certain.”

Photo by Rhoda Baer

A review of data from more than 19 million people indicates that diabetes significantly raises a person’s risk of developing cancer.

When researchers compared patients with diabetes and without, both male and female diabetics had an increased risk of leukemias and lymphomas as well as certain solid tumors.

Researchers also found that diabetes conferred a higher cancer risk for women than men, both for all cancers combined and for some specific cancers, including leukemia.

“The link between diabetes and the risk of developing cancer is now firmly established,” said Toshiaki Ohkuma, PhD, of The George Institute for Global Health at the University of New South Wales in Australia.

“We have also demonstrated, for the first time, that women with diabetes are more likely to develop any form of cancer and have a significantly higher chance of developing kidney, oral, and stomach cancers and leukemia.”

Dr Ohkuma and his colleagues reported these findings in Diabetologia.

The researchers conducted a systematic search in PubMed MEDLINE to identify reports on the links between diabetes and cancer. Additional reports were identified from the reference lists of the relevant studies.

Only those cohort studies providing relative risks (RRs) for the association between diabetes and cancer for both women and men were included. In total, 107 relevant articles were identified, along with 36 cohorts of individual participant data.

RRs for cancer were obtained for patients with diabetes (types 1 and 2 combined) versus those without diabetes, for both men and women. The women-to-men ratios of these relative risk ratios (RRRs) were then calculated to determine the excess risk in women if present.

Data on all-site cancer was available from 47 studies, involving 121 cohorts and 19,239,302 individuals.

Diabetics vs non-diabetics

Women with diabetes had a 27% higher risk of all-site cancer compared to women without diabetes (RR=1.27; 95% CI 1.21, 1.32; P<0.001).

For men, the risk of all-site cancer was 19% higher among those with diabetes than those without (RR=1.19; 95% CI 1.13, 1.25; P<0.001).

There were several hematologic malignancies for which diabetics had an increased risk, as shown in the following table.

Sex comparison

Calculation of the women-to-men ratio revealed that women with diabetes had a 6% greater excess risk of all-site cancer compared to men with diabetes (RRR=1.06; 95% CI 1.03, 1.09; P<0.001).

The women-to-men ratios also showed significantly higher risks for female diabetics for:

• Kidney cancer—RRR=1.11 (99% CI 1.04, 1.18; P<0.001)
• Oral cancer—RRR=1.13 (99% CI 1.00, 1.28; P=0.009)
• Stomach cancer—RRR=1.14 (99% CI 1.07, 1.22; P<0.001)
• Leukemia—RRR=1.15 (99% CI 1.02, 1.28; P=0.002).

However, women had a significantly lower risk of liver cancer (RRR=0.88; 99% CI 0.79, 0.99; P=0.005).

There are several possible reasons for the excess cancer risk observed in women, according to study author Sanne Peters, PhD, of The George Institute for Global Health at the University of Oxford in the UK.

For example, on average, women are in the pre-diabetic state of impaired glucose tolerance 2 years longer than men.

“Historically, we know that women are often under-treated when they first present with symptoms of diabetes, are less likely to receive intensive care, and are not taking the same levels of medications as men,” Dr Peters said. “All of these could go some way into explaining why women are at greater risk of developing cancer, but, without more research, we can’t be certain.”

Respiratory illness was the most common pediatric emergency in ambulatory settings, followed by psychiatric and behavioral illness, seizures, and syncope, according to results published July 20 in Pediatrics.

Investigators conducted a retrospective observational study of data from the Indianapolis emergency medical services (EMS) system between Jan. 1, 2012, and Dec. 31, 2014. All patients younger than 18 years were eligible.

Of 38,841 pediatric EMS transports in the Indianapolis metropolitan area during the 3-year period, fewer than 1% (322) were verified as originating from an ambulatory practice, reported Matthew L. Yuknis, MD, and his coauthors at Indiana University, Indianapolis. Respiratory distress was the most common emergency (58%), followed by psychiatric and behavioral illness (6%), seizure (6%), and syncope (5%).

The most common interventions were use of supplemental oxygen (27%), albuterol (26%), and intravascular access (11%). The most common critical care interventions were administration of fluid bolus (2%), benzodiazepine (2%), or racemic or intramuscular epinephrine (1%). None required use of an artificial airway, cardiopulmonary resuscitation, intraosseous access, or bag mask ventilation, Dr. Yuknis and his colleagues said.

The average time from call to on-scene arrival was 6 minutes (ranging from less than 1 to 15 minutes). The average patient transport time was 13 minutes (ranging from less than 1 to 38 minutes). The average annual frequency of pediatric outpatient emergencies was 42 emergencies per 100,000 people under 18 years of age. Lower socioeconomic status was correlated with increased frequency of emergencies in ambulatory settings, the authors reported.

“These findings update and clarify existing literature with regard to the frequency of pediatric emergencies in the ambulatory setting, the conditions these patients present with, and the use of EMS data to define these events,” the authors wrote. Additionally, the findings can be used to “inform future decisions regarding necessary equipment and procedures.”

No relevant financial disclosures were reported. There was no external funding.

SOURCE: Yuknis M et al. Pediatrics. 2018. doi: 10.1542/peds.2017-3082.

Respiratory illness was the most common pediatric emergency in ambulatory settings, followed by psychiatric and behavioral illness, seizures, and syncope, according to results published July 20 in Pediatrics.

Investigators conducted a retrospective observational study of data from the Indianapolis emergency medical services (EMS) system between Jan. 1, 2012, and Dec. 31, 2014. All patients younger than 18 years were eligible.

Of 38,841 pediatric EMS transports in the Indianapolis metropolitan area during the 3-year period, fewer than 1% (322) were verified as originating from an ambulatory practice, reported Matthew L. Yuknis, MD, and his coauthors at Indiana University, Indianapolis. Respiratory distress was the most common emergency (58%), followed by psychiatric and behavioral illness (6%), seizure (6%), and syncope (5%).

The most common interventions were use of supplemental oxygen (27%), albuterol (26%), and intravascular access (11%). The most common critical care interventions were administration of fluid bolus (2%), benzodiazepine (2%), or racemic or intramuscular epinephrine (1%). None required use of an artificial airway, cardiopulmonary resuscitation, intraosseous access, or bag mask ventilation, Dr. Yuknis and his colleagues said.

The average time from call to on-scene arrival was 6 minutes (ranging from less than 1 to 15 minutes). The average patient transport time was 13 minutes (ranging from less than 1 to 38 minutes). The average annual frequency of pediatric outpatient emergencies was 42 emergencies per 100,000 people under 18 years of age. Lower socioeconomic status was correlated with increased frequency of emergencies in ambulatory settings, the authors reported.

“These findings update and clarify existing literature with regard to the frequency of pediatric emergencies in the ambulatory setting, the conditions these patients present with, and the use of EMS data to define these events,” the authors wrote. Additionally, the findings can be used to “inform future decisions regarding necessary equipment and procedures.”

No relevant financial disclosures were reported. There was no external funding.

SOURCE: Yuknis M et al. Pediatrics. 2018. doi: 10.1542/peds.2017-3082.

Respiratory illness was the most common pediatric emergency in ambulatory settings, followed by psychiatric and behavioral illness, seizures, and syncope, according to results published July 20 in Pediatrics.

Investigators conducted a retrospective observational study of data from the Indianapolis emergency medical services (EMS) system between Jan. 1, 2012, and Dec. 31, 2014. All patients younger than 18 years were eligible.

Of 38,841 pediatric EMS transports in the Indianapolis metropolitan area during the 3-year period, fewer than 1% (322) were verified as originating from an ambulatory practice, reported Matthew L. Yuknis, MD, and his coauthors at Indiana University, Indianapolis. Respiratory distress was the most common emergency (58%), followed by psychiatric and behavioral illness (6%), seizure (6%), and syncope (5%).

The most common interventions were use of supplemental oxygen (27%), albuterol (26%), and intravascular access (11%). The most common critical care interventions were administration of fluid bolus (2%), benzodiazepine (2%), or racemic or intramuscular epinephrine (1%). None required use of an artificial airway, cardiopulmonary resuscitation, intraosseous access, or bag mask ventilation, Dr. Yuknis and his colleagues said.

The average time from call to on-scene arrival was 6 minutes (ranging from less than 1 to 15 minutes). The average patient transport time was 13 minutes (ranging from less than 1 to 38 minutes). The average annual frequency of pediatric outpatient emergencies was 42 emergencies per 100,000 people under 18 years of age. Lower socioeconomic status was correlated with increased frequency of emergencies in ambulatory settings, the authors reported.

“These findings update and clarify existing literature with regard to the frequency of pediatric emergencies in the ambulatory setting, the conditions these patients present with, and the use of EMS data to define these events,” the authors wrote. Additionally, the findings can be used to “inform future decisions regarding necessary equipment and procedures.”

No relevant financial disclosures were reported. There was no external funding.

SOURCE: Yuknis M et al. Pediatrics. 2018. doi: 10.1542/peds.2017-3082.

Children and adults with sickle cell disease who received L-glutamine alone or with hydroxyurea had a median number of pain episodes that was 25% lower than those who received placebo, according to newly published results from the phase 3 trial that led to the agent’s approval in 2017.

The median number of hospitalizations was 33% lower among individuals receiving L-glutamine than it was among those receiving placebo, in results reported by investigators led by Yutaka Niihara, MD, of the University of California, Los Angeles, and Emmaus Medical.

CDC/Janice Haney Carr

Blood test results showed persistent elevation of mean corpuscular volume, indicating adherence to hydroxyurea therapy and suggesting that the effect of L-glutamine might be additive, Dr. Niihara and his coauthors wrote in the New England Journal of Medicine.

“L-glutamine thus provides an alternative therapy for those who decline treatment with hydroxyurea or who may have unacceptable side effects from hydroxyurea, as well as an additive therapy to lower the incidence of pain crises for those who may have suboptimal response to hydroxyurea,” they wrote.

The multicenter, randomized, placebo-controlled, double-blind, phase 3 trial by Dr. Niihara and his colleagues included 230 children and adults with sickle cell anemia or sickle-beta⁰-thalassemia and two or more pain crises in the previous year.

Participants at 31 sites across the United States were randomized to receive L-glutamine powder (n = 152) or placebo (n = 78) orally twice weekly for 48 weeks, followed by a 3-week tapering period. Two-thirds received concomitant hydroxyurea during the trial.

Participants were contacted by telephone weekly during the study to encourage adherence.

A total of 156 individuals completed the study, including 97 of 152 (63.8%) in the L-glutamine arm and 59 of 78 (75.6%) in the placebo arm. The most common reasons for discontinuation were withdrawal of consent, nonadherence, or reasons classified as “other,” according to investigators.

The primary end point was the number of pain crises through week 48 of the trial. A median of 3.0 pain crises occurred in the L-glutamine group, compared with 4.0 in the placebo group (P = .005). Additionally, the median number of hospitalizations was 2.0 for the L-glutamine group versus 3.0 for the placebo group (P = .005).

Nausea, arm or leg pain, and back pain all had an incidence in the L-glutamine group that was 5% higher than in the placebo group, investigators reported.

Based on these results, the Food and Drug administration approved oral L-glutamine powder to reduce the acute complications of sickle cell disease in patients 5 years of age and older in July 2017.

The reasons for study withdrawal were similar in the L-glutamine and placebo groups, despite the higher withdrawal rate in the L-glutamine group, investigators said in a discussion of their results. “Recruitment and retention in a year-long study is difficult in an already burdened population,” they wrote.

The overall noncompletion rate was 32%, similar to the 35% rate seen in a recent multicenter trial of crizanlizumab in patients with sickle cell disease, they added.

Dr. Niihara is the founder and CEO of Emmaus Medical, which sponsored the trial. Other coauthors also reported disclosures related to Emmaus Medical and other companies.

SOURCE: Niihara Y et al. N Engl J Med. 2018 Jul 19;379(3):226-35.

Children and adults with sickle cell disease who received L-glutamine alone or with hydroxyurea had a median number of pain episodes that was 25% lower than those who received placebo, according to newly published results from the phase 3 trial that led to the agent’s approval in 2017.

The median number of hospitalizations was 33% lower among individuals receiving L-glutamine than it was among those receiving placebo, in results reported by investigators led by Yutaka Niihara, MD, of the University of California, Los Angeles, and Emmaus Medical.

CDC/Janice Haney Carr

Blood test results showed persistent elevation of mean corpuscular volume, indicating adherence to hydroxyurea therapy and suggesting that the effect of L-glutamine might be additive, Dr. Niihara and his coauthors wrote in the New England Journal of Medicine.

“L-glutamine thus provides an alternative therapy for those who decline treatment with hydroxyurea or who may have unacceptable side effects from hydroxyurea, as well as an additive therapy to lower the incidence of pain crises for those who may have suboptimal response to hydroxyurea,” they wrote.

The multicenter, randomized, placebo-controlled, double-blind, phase 3 trial by Dr. Niihara and his colleagues included 230 children and adults with sickle cell anemia or sickle-beta⁰-thalassemia and two or more pain crises in the previous year.

Participants at 31 sites across the United States were randomized to receive L-glutamine powder (n = 152) or placebo (n = 78) orally twice weekly for 48 weeks, followed by a 3-week tapering period. Two-thirds received concomitant hydroxyurea during the trial.

Participants were contacted by telephone weekly during the study to encourage adherence.

A total of 156 individuals completed the study, including 97 of 152 (63.8%) in the L-glutamine arm and 59 of 78 (75.6%) in the placebo arm. The most common reasons for discontinuation were withdrawal of consent, nonadherence, or reasons classified as “other,” according to investigators.

The primary end point was the number of pain crises through week 48 of the trial. A median of 3.0 pain crises occurred in the L-glutamine group, compared with 4.0 in the placebo group (P = .005). Additionally, the median number of hospitalizations was 2.0 for the L-glutamine group versus 3.0 for the placebo group (P = .005).

Nausea, arm or leg pain, and back pain all had an incidence in the L-glutamine group that was 5% higher than in the placebo group, investigators reported.

Based on these results, the Food and Drug administration approved oral L-glutamine powder to reduce the acute complications of sickle cell disease in patients 5 years of age and older in July 2017.

The reasons for study withdrawal were similar in the L-glutamine and placebo groups, despite the higher withdrawal rate in the L-glutamine group, investigators said in a discussion of their results. “Recruitment and retention in a year-long study is difficult in an already burdened population,” they wrote.

The overall noncompletion rate was 32%, similar to the 35% rate seen in a recent multicenter trial of crizanlizumab in patients with sickle cell disease, they added.

Dr. Niihara is the founder and CEO of Emmaus Medical, which sponsored the trial. Other coauthors also reported disclosures related to Emmaus Medical and other companies.

SOURCE: Niihara Y et al. N Engl J Med. 2018 Jul 19;379(3):226-35.

Children and adults with sickle cell disease who received L-glutamine alone or with hydroxyurea had a median number of pain episodes that was 25% lower than those who received placebo, according to newly published results from the phase 3 trial that led to the agent’s approval in 2017.

The median number of hospitalizations was 33% lower among individuals receiving L-glutamine than it was among those receiving placebo, in results reported by investigators led by Yutaka Niihara, MD, of the University of California, Los Angeles, and Emmaus Medical.

CDC/Janice Haney Carr

Blood test results showed persistent elevation of mean corpuscular volume, indicating adherence to hydroxyurea therapy and suggesting that the effect of L-glutamine might be additive, Dr. Niihara and his coauthors wrote in the New England Journal of Medicine.

“L-glutamine thus provides an alternative therapy for those who decline treatment with hydroxyurea or who may have unacceptable side effects from hydroxyurea, as well as an additive therapy to lower the incidence of pain crises for those who may have suboptimal response to hydroxyurea,” they wrote.

The multicenter, randomized, placebo-controlled, double-blind, phase 3 trial by Dr. Niihara and his colleagues included 230 children and adults with sickle cell anemia or sickle-beta⁰-thalassemia and two or more pain crises in the previous year.

Participants at 31 sites across the United States were randomized to receive L-glutamine powder (n = 152) or placebo (n = 78) orally twice weekly for 48 weeks, followed by a 3-week tapering period. Two-thirds received concomitant hydroxyurea during the trial.

Participants were contacted by telephone weekly during the study to encourage adherence.

A total of 156 individuals completed the study, including 97 of 152 (63.8%) in the L-glutamine arm and 59 of 78 (75.6%) in the placebo arm. The most common reasons for discontinuation were withdrawal of consent, nonadherence, or reasons classified as “other,” according to investigators.

The primary end point was the number of pain crises through week 48 of the trial. A median of 3.0 pain crises occurred in the L-glutamine group, compared with 4.0 in the placebo group (P = .005). Additionally, the median number of hospitalizations was 2.0 for the L-glutamine group versus 3.0 for the placebo group (P = .005).

Nausea, arm or leg pain, and back pain all had an incidence in the L-glutamine group that was 5% higher than in the placebo group, investigators reported.

Based on these results, the Food and Drug administration approved oral L-glutamine powder to reduce the acute complications of sickle cell disease in patients 5 years of age and older in July 2017.

The reasons for study withdrawal were similar in the L-glutamine and placebo groups, despite the higher withdrawal rate in the L-glutamine group, investigators said in a discussion of their results. “Recruitment and retention in a year-long study is difficult in an already burdened population,” they wrote.

The overall noncompletion rate was 32%, similar to the 35% rate seen in a recent multicenter trial of crizanlizumab in patients with sickle cell disease, they added.

Dr. Niihara is the founder and CEO of Emmaus Medical, which sponsored the trial. Other coauthors also reported disclosures related to Emmaus Medical and other companies.

SOURCE: Niihara Y et al. N Engl J Med. 2018 Jul 19;379(3):226-35.

CHICAGO – Oncology biosimilars for bevacizumab (Avastin), trastuzumab (Herceptin), and filgrastim (Neupogen and others) have yielded positive results in various patient populations and clinical settings, investigators reported at the annual meeting of the American Society of Clinical Oncology. The findings further advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.

Susan London/MDedge News

Bevacizumab biosimilar

The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous NSCLC. Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.

Susan London/MDedge News

Trastuzumab biosimilar

The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer.

The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various adverse events were essentially the same.

Susan London/MDedge News

Filgrastim biosimilar

Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of ob&gyn at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony–stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.

Susan London/MDedge News

SOURCE: Socinski MA et al. ASCO 2018, Abstract 109. Manikhas A et al. ASCO 2018, Abstract 110. Harbeck N et al. ASCO 2018, Abstract 111.

CHICAGO – Oncology biosimilars for bevacizumab (Avastin), trastuzumab (Herceptin), and filgrastim (Neupogen and others) have yielded positive results in various patient populations and clinical settings, investigators reported at the annual meeting of the American Society of Clinical Oncology. The findings further advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.

Susan London/MDedge News

Bevacizumab biosimilar

The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous NSCLC. Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.

Susan London/MDedge News

Trastuzumab biosimilar

The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer.

The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various adverse events were essentially the same.

Susan London/MDedge News

Filgrastim biosimilar

Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of ob&gyn at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony–stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.

Susan London/MDedge News

SOURCE: Socinski MA et al. ASCO 2018, Abstract 109. Manikhas A et al. ASCO 2018, Abstract 110. Harbeck N et al. ASCO 2018, Abstract 111.

CHICAGO – Oncology biosimilars for bevacizumab (Avastin), trastuzumab (Herceptin), and filgrastim (Neupogen and others) have yielded positive results in various patient populations and clinical settings, investigators reported at the annual meeting of the American Society of Clinical Oncology. The findings further advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.

Susan London/MDedge News

Bevacizumab biosimilar

The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous NSCLC. Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.

Susan London/MDedge News

Trastuzumab biosimilar

The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer.

The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various adverse events were essentially the same.

Susan London/MDedge News

Filgrastim biosimilar

Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of ob&gyn at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony–stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.

Susan London/MDedge News

SOURCE: Socinski MA et al. ASCO 2018, Abstract 109. Manikhas A et al. ASCO 2018, Abstract 110. Harbeck N et al. ASCO 2018, Abstract 111.

Think of opioid use disorder as a chronic condition that requires continuous treatment.

This advice comes from Mitra Ahadpour, MD, who is the deputy director of the Office of Translational Sciences at the Food and Drug Administration’s Center for Drug Evaluation and Research and an addiction medicine specialist.

In an interview, Dr. Ahadpour discusses prescribing requirements and the administration of drugs for medication-assisted treatment, which is associated with improved social functioning and reduced risks for death from overdoses and by contracting HIV.

These treatments – which include various formulations of methadone, buprenorphine, and naltrexone – need to reach more people with opioid use disorder. The interview includes her recommendations for recognizing at-risk patients and avoiding potential drug-drug interactions associated with using these drugs.

Click here to read the article at the FDA website.

Think of opioid use disorder as a chronic condition that requires continuous treatment.

This advice comes from Mitra Ahadpour, MD, who is the deputy director of the Office of Translational Sciences at the Food and Drug Administration’s Center for Drug Evaluation and Research and an addiction medicine specialist.

In an interview, Dr. Ahadpour discusses prescribing requirements and the administration of drugs for medication-assisted treatment, which is associated with improved social functioning and reduced risks for death from overdoses and by contracting HIV.

These treatments – which include various formulations of methadone, buprenorphine, and naltrexone – need to reach more people with opioid use disorder. The interview includes her recommendations for recognizing at-risk patients and avoiding potential drug-drug interactions associated with using these drugs.

Click here to read the article at the FDA website.

Think of opioid use disorder as a chronic condition that requires continuous treatment.

This advice comes from Mitra Ahadpour, MD, who is the deputy director of the Office of Translational Sciences at the Food and Drug Administration’s Center for Drug Evaluation and Research and an addiction medicine specialist.

In an interview, Dr. Ahadpour discusses prescribing requirements and the administration of drugs for medication-assisted treatment, which is associated with improved social functioning and reduced risks for death from overdoses and by contracting HIV.

These treatments – which include various formulations of methadone, buprenorphine, and naltrexone – need to reach more people with opioid use disorder. The interview includes her recommendations for recognizing at-risk patients and avoiding potential drug-drug interactions associated with using these drugs.

Click here to read the article at the FDA website.