Henrique Orlandi Mourao

Researchers say they have discovered a way to target the transcription factor MEF2C in acute myeloid leukemia (AML).

The team found they could stop the growth of MEF2C-driven AML cells by blocking either LKB1 or the salt-inducible kinases SIK3 and SIK2.

Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described this research in Molecular Cell.

The current discoveries are the result of a broad search for potential therapeutic strategies against AML that began several years ago in Dr Vakoc’s lab.

In 2013, his team devised a system based on CRISPR gene editing tools. They used this system to screen large numbers of genes, seeking to discover their impact on cancer cell survival.

Now, the system has revealed that LKB1 and SIK are critical for the survival of certain AML cells. These enzymes had not previously been linked to AML, but the researchers learned that LKB1 and SIK help control MEF2C.

The team observed overlapping LKB1, SIK, and MEF2C dependencies in AML cell lines, particularly MLL fusion lines (MOLM-13, MV4-11, NOMO-1, and THP-1). And the researchers found the transcriptional output of MEF2C could be suppressed by inhibition of LKB1 or SIK.

“At the end of project, we realized we’d actually discovered a way to control a transcription factor,” Dr Vakoc said.

He and his colleagues found that SIK3 inactivation had the strongest effect on MEF2C. Two hours of exposure to the SIK inhibitor HG-9-91-01 (100 nM) was enough to suppress the MEF2C signature.

The researchers also noted that the effect of SIK3 targeting on transcription was attenuated if it was performed in cells deficient in HDAC4. This and related findings suggested that LKB1-SIK3 signaling supports the transcriptional output of MEF2C through inhibition of HDAC4.

Dr Vakoc and his colleagues said the “potency and selectivity of AML growth arrest” they observed after targeting LKB1 or SIK2 and SIK3 resembles the effects of targeting other validated kinase oncogenes in AML, such as FLT3.

The team also said the sensitivity of AML cell lines to HG-9-91-01 “compares favorably” to the sensitivity of cancer cell lines to kinase inhibitors already approved for oncology indications. However, “additional optimization” of HG-9-91-01 is needed.

Henrique Orlandi Mourao

Researchers say they have discovered a way to target the transcription factor MEF2C in acute myeloid leukemia (AML).

The team found they could stop the growth of MEF2C-driven AML cells by blocking either LKB1 or the salt-inducible kinases SIK3 and SIK2.

Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described this research in Molecular Cell.

The current discoveries are the result of a broad search for potential therapeutic strategies against AML that began several years ago in Dr Vakoc’s lab.

In 2013, his team devised a system based on CRISPR gene editing tools. They used this system to screen large numbers of genes, seeking to discover their impact on cancer cell survival.

Now, the system has revealed that LKB1 and SIK are critical for the survival of certain AML cells. These enzymes had not previously been linked to AML, but the researchers learned that LKB1 and SIK help control MEF2C.

The team observed overlapping LKB1, SIK, and MEF2C dependencies in AML cell lines, particularly MLL fusion lines (MOLM-13, MV4-11, NOMO-1, and THP-1). And the researchers found the transcriptional output of MEF2C could be suppressed by inhibition of LKB1 or SIK.

“At the end of project, we realized we’d actually discovered a way to control a transcription factor,” Dr Vakoc said.

He and his colleagues found that SIK3 inactivation had the strongest effect on MEF2C. Two hours of exposure to the SIK inhibitor HG-9-91-01 (100 nM) was enough to suppress the MEF2C signature.

The researchers also noted that the effect of SIK3 targeting on transcription was attenuated if it was performed in cells deficient in HDAC4. This and related findings suggested that LKB1-SIK3 signaling supports the transcriptional output of MEF2C through inhibition of HDAC4.

Dr Vakoc and his colleagues said the “potency and selectivity of AML growth arrest” they observed after targeting LKB1 or SIK2 and SIK3 resembles the effects of targeting other validated kinase oncogenes in AML, such as FLT3.

The team also said the sensitivity of AML cell lines to HG-9-91-01 “compares favorably” to the sensitivity of cancer cell lines to kinase inhibitors already approved for oncology indications. However, “additional optimization” of HG-9-91-01 is needed.

Henrique Orlandi Mourao

Researchers say they have discovered a way to target the transcription factor MEF2C in acute myeloid leukemia (AML).

The team found they could stop the growth of MEF2C-driven AML cells by blocking either LKB1 or the salt-inducible kinases SIK3 and SIK2.

Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described this research in Molecular Cell.

The current discoveries are the result of a broad search for potential therapeutic strategies against AML that began several years ago in Dr Vakoc’s lab.

In 2013, his team devised a system based on CRISPR gene editing tools. They used this system to screen large numbers of genes, seeking to discover their impact on cancer cell survival.

Now, the system has revealed that LKB1 and SIK are critical for the survival of certain AML cells. These enzymes had not previously been linked to AML, but the researchers learned that LKB1 and SIK help control MEF2C.

The team observed overlapping LKB1, SIK, and MEF2C dependencies in AML cell lines, particularly MLL fusion lines (MOLM-13, MV4-11, NOMO-1, and THP-1). And the researchers found the transcriptional output of MEF2C could be suppressed by inhibition of LKB1 or SIK.

“At the end of project, we realized we’d actually discovered a way to control a transcription factor,” Dr Vakoc said.

He and his colleagues found that SIK3 inactivation had the strongest effect on MEF2C. Two hours of exposure to the SIK inhibitor HG-9-91-01 (100 nM) was enough to suppress the MEF2C signature.

The researchers also noted that the effect of SIK3 targeting on transcription was attenuated if it was performed in cells deficient in HDAC4. This and related findings suggested that LKB1-SIK3 signaling supports the transcriptional output of MEF2C through inhibition of HDAC4.

Dr Vakoc and his colleagues said the “potency and selectivity of AML growth arrest” they observed after targeting LKB1 or SIK2 and SIK3 resembles the effects of targeting other validated kinase oncogenes in AML, such as FLT3.

The team also said the sensitivity of AML cell lines to HG-9-91-01 “compares favorably” to the sensitivity of cancer cell lines to kinase inhibitors already approved for oncology indications. However, “additional optimization” of HG-9-91-01 is needed.

Photo by Esther Dyson

A new study has revealed discrepancies in completion status for trials listed on ClinicalTrials.gov and the EU Clinical Trials Register (EUCTR).

Researchers evaluated nearly 10,500 trials listed on both registries and found that roughly 16% of them were marked as “completed” on one registry and “ongoing” on the other.

Most of these (91%) were listed as “ongoing” on EUCTR but “completed” on ClinicalTrials.gov.

“Trial registries are important public documents,” said Ben Goldacre, of the University of Oxford in the UK.

“Doctors, researchers, and patients rely on the information that trialists post about their clinical trial. Concerningly, we now show that this data is commonly inaccurate.”

Goldacre and his colleague, Jessica Fleminger, also from the University of Oxford, reported these findings in PLOS ONE.

The researchers looked at 10,492 clinical trials that were registered on both ClinicalTrials.gov and EUCTR.

For most of these trials (83.8%, n=8794), completion status was the same on both registries. But there were 1698 trials (16.2%) that were listed as “completed” on one registry and “ongoing” on another.

A majority of the discrepant trials (90.5%, n=1536) were “ongoing” on EUCTR and “complete” on ClinicalTrials.gov.

Overall, 43.1% (4530/10,492) of dual-registered trials were listed as “ongoing” on EUCTR, and 33.9% of these (1536/4530) were listed as “completed” on ClinicalTrials.gov.

Thirty percent (3156/10,492) of dual-registered trials were marked as “ongoing” on ClinicalTrials.gov, and 5.1% (162/3156) of these were marked as “completed” on EUCTR.

Goldacre and Fleminger said it is unclear whether researchers, registry owners, or both are responsible for these errors. Regardless, researchers identifying discrepancies should request clarifications from the trialists, and registry owners should undertake simple cross-checks of data to ensure that completion status is accurate.

Photo by Esther Dyson

A new study has revealed discrepancies in completion status for trials listed on ClinicalTrials.gov and the EU Clinical Trials Register (EUCTR).

Researchers evaluated nearly 10,500 trials listed on both registries and found that roughly 16% of them were marked as “completed” on one registry and “ongoing” on the other.

Most of these (91%) were listed as “ongoing” on EUCTR but “completed” on ClinicalTrials.gov.

“Trial registries are important public documents,” said Ben Goldacre, of the University of Oxford in the UK.

“Doctors, researchers, and patients rely on the information that trialists post about their clinical trial. Concerningly, we now show that this data is commonly inaccurate.”

Goldacre and his colleague, Jessica Fleminger, also from the University of Oxford, reported these findings in PLOS ONE.

The researchers looked at 10,492 clinical trials that were registered on both ClinicalTrials.gov and EUCTR.

For most of these trials (83.8%, n=8794), completion status was the same on both registries. But there were 1698 trials (16.2%) that were listed as “completed” on one registry and “ongoing” on another.

A majority of the discrepant trials (90.5%, n=1536) were “ongoing” on EUCTR and “complete” on ClinicalTrials.gov.

Overall, 43.1% (4530/10,492) of dual-registered trials were listed as “ongoing” on EUCTR, and 33.9% of these (1536/4530) were listed as “completed” on ClinicalTrials.gov.

Thirty percent (3156/10,492) of dual-registered trials were marked as “ongoing” on ClinicalTrials.gov, and 5.1% (162/3156) of these were marked as “completed” on EUCTR.

Goldacre and Fleminger said it is unclear whether researchers, registry owners, or both are responsible for these errors. Regardless, researchers identifying discrepancies should request clarifications from the trialists, and registry owners should undertake simple cross-checks of data to ensure that completion status is accurate.

Photo by Esther Dyson

A new study has revealed discrepancies in completion status for trials listed on ClinicalTrials.gov and the EU Clinical Trials Register (EUCTR).

Researchers evaluated nearly 10,500 trials listed on both registries and found that roughly 16% of them were marked as “completed” on one registry and “ongoing” on the other.

Most of these (91%) were listed as “ongoing” on EUCTR but “completed” on ClinicalTrials.gov.

“Trial registries are important public documents,” said Ben Goldacre, of the University of Oxford in the UK.

“Doctors, researchers, and patients rely on the information that trialists post about their clinical trial. Concerningly, we now show that this data is commonly inaccurate.”

Goldacre and his colleague, Jessica Fleminger, also from the University of Oxford, reported these findings in PLOS ONE.

The researchers looked at 10,492 clinical trials that were registered on both ClinicalTrials.gov and EUCTR.

For most of these trials (83.8%, n=8794), completion status was the same on both registries. But there were 1698 trials (16.2%) that were listed as “completed” on one registry and “ongoing” on another.

A majority of the discrepant trials (90.5%, n=1536) were “ongoing” on EUCTR and “complete” on ClinicalTrials.gov.

Overall, 43.1% (4530/10,492) of dual-registered trials were listed as “ongoing” on EUCTR, and 33.9% of these (1536/4530) were listed as “completed” on ClinicalTrials.gov.

Thirty percent (3156/10,492) of dual-registered trials were marked as “ongoing” on ClinicalTrials.gov, and 5.1% (162/3156) of these were marked as “completed” on EUCTR.

Goldacre and Fleminger said it is unclear whether researchers, registry owners, or both are responsible for these errors. Regardless, researchers identifying discrepancies should request clarifications from the trialists, and registry owners should undertake simple cross-checks of data to ensure that completion status is accurate.

Nordestgaard, B.G., J Am Coll Cardiol 70(13):1637, September 26, 2017

This Danish author reviews the impact of a fasting versus nonfasting state on lipid profile testing. He addresses the pros and cons of fasting or nonfasting lipid profiles, the impact on individual lipid parameters, and the implications for diagnosing and treating cardiovascular disease (CVD). Testing lipid profiles in the nonfasting state is increasingly common, in part because it is simpler, given that (typically) 16 hours per day are nonfasting. In addition, a nonfasting lipid profile is more accurate for measuring total atherogenic lipoproteins in plasma because it includes those of hepatic origin in the fasting state and those of intestinal origin in the nonfasting state. Maximum mean differences in lipid parameters measured in nonfasting versus fasting patients are +26mg/dL for triglycerides, -8mg/dL for total cholesterol, -8mg/dL for LDL cholesterol, +8mg/dL for remnant cholesterol, and -8mg/dL for non-HDL cholesterol. The reductions in total, LDL and non-HDL cholesterol are mainly due to fluid intake and not food consumption. A nonfasting condition has no appreciable effect on HDL cholesterol, lipoprotein(a), or apolipoproteins A1 and B. Nonfasting lipid profiles have equal predictive ability for CVD and should not affect treatment decisions (e.g., statin use) for most patients. Testing of nonfasting samples is simpler for all parties (patients, clinicians and laboratories), safer for patients who cannot fast, increases efficiency, and saves money. International guidelines since 2009 are increasingly recommending nonfasting lipid profiles. The author notes that testing of fasting lipid profiles continues largely because “we have always done it this way.” He recommends that nonfasting blood samples be routinely tested, except in selected patients who require fasting samples. 55 references ([email protected] – no reprints)

Nordestgaard, B.G., J Am Coll Cardiol 70(13):1637, September 26, 2017

This Danish author reviews the impact of a fasting versus nonfasting state on lipid profile testing. He addresses the pros and cons of fasting or nonfasting lipid profiles, the impact on individual lipid parameters, and the implications for diagnosing and treating cardiovascular disease (CVD). Testing lipid profiles in the nonfasting state is increasingly common, in part because it is simpler, given that (typically) 16 hours per day are nonfasting. In addition, a nonfasting lipid profile is more accurate for measuring total atherogenic lipoproteins in plasma because it includes those of hepatic origin in the fasting state and those of intestinal origin in the nonfasting state. Maximum mean differences in lipid parameters measured in nonfasting versus fasting patients are +26mg/dL for triglycerides, -8mg/dL for total cholesterol, -8mg/dL for LDL cholesterol, +8mg/dL for remnant cholesterol, and -8mg/dL for non-HDL cholesterol. The reductions in total, LDL and non-HDL cholesterol are mainly due to fluid intake and not food consumption. A nonfasting condition has no appreciable effect on HDL cholesterol, lipoprotein(a), or apolipoproteins A1 and B. Nonfasting lipid profiles have equal predictive ability for CVD and should not affect treatment decisions (e.g., statin use) for most patients. Testing of nonfasting samples is simpler for all parties (patients, clinicians and laboratories), safer for patients who cannot fast, increases efficiency, and saves money. International guidelines since 2009 are increasingly recommending nonfasting lipid profiles. The author notes that testing of fasting lipid profiles continues largely because “we have always done it this way.” He recommends that nonfasting blood samples be routinely tested, except in selected patients who require fasting samples. 55 references ([email protected] – no reprints)

Nordestgaard, B.G., J Am Coll Cardiol 70(13):1637, September 26, 2017

This Danish author reviews the impact of a fasting versus nonfasting state on lipid profile testing. He addresses the pros and cons of fasting or nonfasting lipid profiles, the impact on individual lipid parameters, and the implications for diagnosing and treating cardiovascular disease (CVD). Testing lipid profiles in the nonfasting state is increasingly common, in part because it is simpler, given that (typically) 16 hours per day are nonfasting. In addition, a nonfasting lipid profile is more accurate for measuring total atherogenic lipoproteins in plasma because it includes those of hepatic origin in the fasting state and those of intestinal origin in the nonfasting state. Maximum mean differences in lipid parameters measured in nonfasting versus fasting patients are +26mg/dL for triglycerides, -8mg/dL for total cholesterol, -8mg/dL for LDL cholesterol, +8mg/dL for remnant cholesterol, and -8mg/dL for non-HDL cholesterol. The reductions in total, LDL and non-HDL cholesterol are mainly due to fluid intake and not food consumption. A nonfasting condition has no appreciable effect on HDL cholesterol, lipoprotein(a), or apolipoproteins A1 and B. Nonfasting lipid profiles have equal predictive ability for CVD and should not affect treatment decisions (e.g., statin use) for most patients. Testing of nonfasting samples is simpler for all parties (patients, clinicians and laboratories), safer for patients who cannot fast, increases efficiency, and saves money. International guidelines since 2009 are increasingly recommending nonfasting lipid profiles. The author notes that testing of fasting lipid profiles continues largely because “we have always done it this way.” He recommends that nonfasting blood samples be routinely tested, except in selected patients who require fasting samples. 55 references ([email protected] – no reprints)

Q) How do you monitor for infection in patients with multiple sclerosis who take disease-modifying therapies?

The answer to this question is “it depends”—on several factors, including current and previous use of disease-modifying therapies (DMTs), concomitant medications, comorbidities, vaccination history, presence of John Cunningham virus (JCV) antibodies (in the case of natalizumab use), and prior or current use of immunosuppressive therapies.

There are many FDA-approved DMTs for multiple sclerosis (MS). Each has a different rate of infection occurring in clinical trials and varying requirements and/or recommendations for safety monitoring. The package inserts for each DMT offer some guidance for clinicians.

Injectable therapies. For two in­terferon therapies—­interferon ß-1b SC and interferon ß-1a—it is recommended to order a complete blood count (CBC), blood chemistry, and liver function tests (LFTs) at baseline, then again at one, three, and six months, and then at ­clinician discretion thereafter.^1,2 For peginterferon ß-1a, ordering a CBC, basic chemistry, and LFTs, at the clinician’s discretion, is advised.³ The package insert for interferon ß-1a IM does not offer specific recommendations for routine safety monitoring.⁴

The package insert for glatiramer acetate offers no recommendations for routine safety monitoring.⁵

In patients for whom two or more DMTs have failed to work, the monoclonal antibody daclizumab may be indicated. Compared to placebo and active comparator, this drug was associated with a higher risk for infection in clinical trials. The most commonly observed types were upper respiratory, urinary tract, and viral infections. There are no recommendations for CBC monitoring with daclizumab, but monthly LFTs are required due to increased risk for hepatic injury.⁶

Oral DMTs. Patients taking fingolimod, teriflunomide, and dimethyl fumarate have increased risk for infection; as a result, there are more safety monitoring recommendations for these medications.^7-9

Prior to starting therapy with fingolimod, baseline CBC, blood chemistries, and varicella antibody testing should be done. ­During therapy, routine CBC testing and LFTs are advised at the clinician’s discretion or if the patient exhibits signs and symptoms of infection (see Table). In clinical trials, fingolimod use was interrupted if the lymphocyte count was sustained at < 200. In rare cases, progressive multifocal leukoencephalopathy (PML) has occurred—so the patient’s age, JCV antibody status, prior use of immunosuppressant therapy, and length of fingolimod treatment should be taken into consideration.⁷

Patients starting teriflunomide should have baseline LFTs and CBC and tuberculosis (TB) testing (either skin or serum), with subsequent monthly LFTs for the first six months on treatment. Some patients may experience neutropenia, thrombocytopenia, and lymphopenia. As a result, patients may have an increased risk for infection. Safety monitoring is at the clinician’s discretion.⁸

For patients initiating dimethyl fumarate, a baseline CBC is recommended, to be repeated every six to 12 months thereafter, and/or as clinically indicated. Since lymphopenia may occur, consider interruption of dimethyl fumarate in patients with lymphocyte counts < 0.5 persisting for more than six months. Rare cases of PML have also occurred; at the first suggestive sign or symptom, dimethyl fumarate should be withheld and appropriate diagnostic testing should be completed.⁹

Natalizumab is an integrin receptor antagonist administered in monthly IV infusions. Patients receiving natalizumab may have increased risk for urinary tract infections, lower respiratory infections, gastroenteritis, vaginitis, and herpes infections. These risks should be monitored at the clinician’s discretion. There have been several cases of PML associated with natalizumab; risk factors include duration of therapy, prior use of immunosuppressants, and presence of JCV antibodies.¹¹

Alemtuzumab is a CD52-directed monoclonal antibody indicated in patients with relapsing forms of MS who have had an inadequate response to at least two DMTs. In clinical trials, subjects had a higher risk for nasopharyngitis, urinary tract infections, upper respiratory infections, sinusitis, herpetic infections, influenza, and bronchitis. Due to the increased risk for infection and secondary autoimmunities, patients are required to have monthly CBC testing, LFTs, and urinalysis for up to 48 months after their last infusion.¹²

Lastly, ocrelizumab is a CD20-directed cytolytic antibody for the treatment of relapsing and progressive forms of MS. In clinical trials, there was a higher incidence of upper and lower respiratory infections, skin infections, and herpes-related infections. Prior to initiating ocrelizumab, hepatitis B virus screening should be completed. There are no specific recommendations for routine monitoring during therapy, although providers should monitor patients clinically for any signs and symptoms of infection.¹³

A word of caution: The common signs and symptoms of infection are listed in the Table. If these symptoms are present in your patient, consider ordering diagnostic testing to evaluate for infection.

Symptoms of PML include progressive unilateral weakness, clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. At the first sign or symptom suggestive of PML, the DMT should be discontinued and diagnostic testing performed.

Providers may contact the manufacturer directly for further guidance on DMT surveillance and treatment protocols. —CK

Christen Kutz, PhD, PA-C
Colorado Springs Neurological Associates

Q) How do you monitor for infection in patients with multiple sclerosis who take disease-modifying therapies?

The answer to this question is “it depends”—on several factors, including current and previous use of disease-modifying therapies (DMTs), concomitant medications, comorbidities, vaccination history, presence of John Cunningham virus (JCV) antibodies (in the case of natalizumab use), and prior or current use of immunosuppressive therapies.

There are many FDA-approved DMTs for multiple sclerosis (MS). Each has a different rate of infection occurring in clinical trials and varying requirements and/or recommendations for safety monitoring. The package inserts for each DMT offer some guidance for clinicians.

Injectable therapies. For two in­terferon therapies—­interferon ß-1b SC and interferon ß-1a—it is recommended to order a complete blood count (CBC), blood chemistry, and liver function tests (LFTs) at baseline, then again at one, three, and six months, and then at ­clinician discretion thereafter.^1,2 For peginterferon ß-1a, ordering a CBC, basic chemistry, and LFTs, at the clinician’s discretion, is advised.³ The package insert for interferon ß-1a IM does not offer specific recommendations for routine safety monitoring.⁴

The package insert for glatiramer acetate offers no recommendations for routine safety monitoring.⁵

In patients for whom two or more DMTs have failed to work, the monoclonal antibody daclizumab may be indicated. Compared to placebo and active comparator, this drug was associated with a higher risk for infection in clinical trials. The most commonly observed types were upper respiratory, urinary tract, and viral infections. There are no recommendations for CBC monitoring with daclizumab, but monthly LFTs are required due to increased risk for hepatic injury.⁶

Oral DMTs. Patients taking fingolimod, teriflunomide, and dimethyl fumarate have increased risk for infection; as a result, there are more safety monitoring recommendations for these medications.^7-9

Prior to starting therapy with fingolimod, baseline CBC, blood chemistries, and varicella antibody testing should be done. ­During therapy, routine CBC testing and LFTs are advised at the clinician’s discretion or if the patient exhibits signs and symptoms of infection (see Table). In clinical trials, fingolimod use was interrupted if the lymphocyte count was sustained at < 200. In rare cases, progressive multifocal leukoencephalopathy (PML) has occurred—so the patient’s age, JCV antibody status, prior use of immunosuppressant therapy, and length of fingolimod treatment should be taken into consideration.⁷

Patients starting teriflunomide should have baseline LFTs and CBC and tuberculosis (TB) testing (either skin or serum), with subsequent monthly LFTs for the first six months on treatment. Some patients may experience neutropenia, thrombocytopenia, and lymphopenia. As a result, patients may have an increased risk for infection. Safety monitoring is at the clinician’s discretion.⁸

For patients initiating dimethyl fumarate, a baseline CBC is recommended, to be repeated every six to 12 months thereafter, and/or as clinically indicated. Since lymphopenia may occur, consider interruption of dimethyl fumarate in patients with lymphocyte counts < 0.5 persisting for more than six months. Rare cases of PML have also occurred; at the first suggestive sign or symptom, dimethyl fumarate should be withheld and appropriate diagnostic testing should be completed.⁹

Natalizumab is an integrin receptor antagonist administered in monthly IV infusions. Patients receiving natalizumab may have increased risk for urinary tract infections, lower respiratory infections, gastroenteritis, vaginitis, and herpes infections. These risks should be monitored at the clinician’s discretion. There have been several cases of PML associated with natalizumab; risk factors include duration of therapy, prior use of immunosuppressants, and presence of JCV antibodies.¹¹

Alemtuzumab is a CD52-directed monoclonal antibody indicated in patients with relapsing forms of MS who have had an inadequate response to at least two DMTs. In clinical trials, subjects had a higher risk for nasopharyngitis, urinary tract infections, upper respiratory infections, sinusitis, herpetic infections, influenza, and bronchitis. Due to the increased risk for infection and secondary autoimmunities, patients are required to have monthly CBC testing, LFTs, and urinalysis for up to 48 months after their last infusion.¹²

Lastly, ocrelizumab is a CD20-directed cytolytic antibody for the treatment of relapsing and progressive forms of MS. In clinical trials, there was a higher incidence of upper and lower respiratory infections, skin infections, and herpes-related infections. Prior to initiating ocrelizumab, hepatitis B virus screening should be completed. There are no specific recommendations for routine monitoring during therapy, although providers should monitor patients clinically for any signs and symptoms of infection.¹³

A word of caution: The common signs and symptoms of infection are listed in the Table. If these symptoms are present in your patient, consider ordering diagnostic testing to evaluate for infection.

Symptoms of PML include progressive unilateral weakness, clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. At the first sign or symptom suggestive of PML, the DMT should be discontinued and diagnostic testing performed.

Providers may contact the manufacturer directly for further guidance on DMT surveillance and treatment protocols. —CK

Christen Kutz, PhD, PA-C
Colorado Springs Neurological Associates

Q) How do you monitor for infection in patients with multiple sclerosis who take disease-modifying therapies?

The answer to this question is “it depends”—on several factors, including current and previous use of disease-modifying therapies (DMTs), concomitant medications, comorbidities, vaccination history, presence of John Cunningham virus (JCV) antibodies (in the case of natalizumab use), and prior or current use of immunosuppressive therapies.

There are many FDA-approved DMTs for multiple sclerosis (MS). Each has a different rate of infection occurring in clinical trials and varying requirements and/or recommendations for safety monitoring. The package inserts for each DMT offer some guidance for clinicians.

Injectable therapies. For two in­terferon therapies—­interferon ß-1b SC and interferon ß-1a—it is recommended to order a complete blood count (CBC), blood chemistry, and liver function tests (LFTs) at baseline, then again at one, three, and six months, and then at ­clinician discretion thereafter.^1,2 For peginterferon ß-1a, ordering a CBC, basic chemistry, and LFTs, at the clinician’s discretion, is advised.³ The package insert for interferon ß-1a IM does not offer specific recommendations for routine safety monitoring.⁴

The package insert for glatiramer acetate offers no recommendations for routine safety monitoring.⁵

In patients for whom two or more DMTs have failed to work, the monoclonal antibody daclizumab may be indicated. Compared to placebo and active comparator, this drug was associated with a higher risk for infection in clinical trials. The most commonly observed types were upper respiratory, urinary tract, and viral infections. There are no recommendations for CBC monitoring with daclizumab, but monthly LFTs are required due to increased risk for hepatic injury.⁶

Oral DMTs. Patients taking fingolimod, teriflunomide, and dimethyl fumarate have increased risk for infection; as a result, there are more safety monitoring recommendations for these medications.^7-9

Prior to starting therapy with fingolimod, baseline CBC, blood chemistries, and varicella antibody testing should be done. ­During therapy, routine CBC testing and LFTs are advised at the clinician’s discretion or if the patient exhibits signs and symptoms of infection (see Table). In clinical trials, fingolimod use was interrupted if the lymphocyte count was sustained at < 200. In rare cases, progressive multifocal leukoencephalopathy (PML) has occurred—so the patient’s age, JCV antibody status, prior use of immunosuppressant therapy, and length of fingolimod treatment should be taken into consideration.⁷

Patients starting teriflunomide should have baseline LFTs and CBC and tuberculosis (TB) testing (either skin or serum), with subsequent monthly LFTs for the first six months on treatment. Some patients may experience neutropenia, thrombocytopenia, and lymphopenia. As a result, patients may have an increased risk for infection. Safety monitoring is at the clinician’s discretion.⁸

For patients initiating dimethyl fumarate, a baseline CBC is recommended, to be repeated every six to 12 months thereafter, and/or as clinically indicated. Since lymphopenia may occur, consider interruption of dimethyl fumarate in patients with lymphocyte counts < 0.5 persisting for more than six months. Rare cases of PML have also occurred; at the first suggestive sign or symptom, dimethyl fumarate should be withheld and appropriate diagnostic testing should be completed.⁹

Natalizumab is an integrin receptor antagonist administered in monthly IV infusions. Patients receiving natalizumab may have increased risk for urinary tract infections, lower respiratory infections, gastroenteritis, vaginitis, and herpes infections. These risks should be monitored at the clinician’s discretion. There have been several cases of PML associated with natalizumab; risk factors include duration of therapy, prior use of immunosuppressants, and presence of JCV antibodies.¹¹

Alemtuzumab is a CD52-directed monoclonal antibody indicated in patients with relapsing forms of MS who have had an inadequate response to at least two DMTs. In clinical trials, subjects had a higher risk for nasopharyngitis, urinary tract infections, upper respiratory infections, sinusitis, herpetic infections, influenza, and bronchitis. Due to the increased risk for infection and secondary autoimmunities, patients are required to have monthly CBC testing, LFTs, and urinalysis for up to 48 months after their last infusion.¹²

Lastly, ocrelizumab is a CD20-directed cytolytic antibody for the treatment of relapsing and progressive forms of MS. In clinical trials, there was a higher incidence of upper and lower respiratory infections, skin infections, and herpes-related infections. Prior to initiating ocrelizumab, hepatitis B virus screening should be completed. There are no specific recommendations for routine monitoring during therapy, although providers should monitor patients clinically for any signs and symptoms of infection.¹³

A word of caution: The common signs and symptoms of infection are listed in the Table. If these symptoms are present in your patient, consider ordering diagnostic testing to evaluate for infection.

Symptoms of PML include progressive unilateral weakness, clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. At the first sign or symptom suggestive of PML, the DMT should be discontinued and diagnostic testing performed.

Providers may contact the manufacturer directly for further guidance on DMT surveillance and treatment protocols. —CK

Christen Kutz, PhD, PA-C
Colorado Springs Neurological Associates

TAMPA – The secret to optimal long-term disease control in schizophrenia is to implement the same type of continuous and close management provided to other chronic diseases, like hypertension or inflammatory bowel disease, according to a lecture delivered at the annual meeting of the American College of Psychiatrists.

In the Dean Award Lecture – a talk characterized as “a stroll through the long-term understanding of the treatment of schizophrenia” – Ira D. Glick, MD, said that, although antipsychotics provide the foundation of disease control, patients and families need to understand and respect disease chronicity.

“What I found in a relatively large sample was that the more adherent patients were to their medication, the more likely they were to report adequate satisfaction with their life,” Dr. Glick said. For those who were not adherent, life in general “has been a disaster.”

This finding is not entirely surprising given the power of antipsychotics to change thinking. However, for those engaged in the immediate task of controlling acute symptoms, the importance of chronicity might not be given adequate emphasis. This requires educating patients and their families about the need to embark on lifetime treatment, Dr. Glick said. Like a diagnosis of diabetes, a diagnosis of schizophrenia means constant vigilance for manifestations of disease and appropriate adjustments of therapy to improve long-term outcomes.

Since evaluating the relationship between medication adherence and long-term outcomes in patients with schizophrenia treated at Stanford, the same type of evaluation was conducted with population samples from the Veterans Affairs system and from China. The data “show exactly the same thing,” Dr. Glick said.

It is important to use every available resource in helping patients recognize and deal with schizophrenia chronicity. In addition to engaging families, he believes that organizations such as the National Alliance on Mental Illness or NAMI, are useful sources of support.

Earlier in his career, Dr. Glick participated in a randomized clinical trial of hospitalization for patients with schizophrenia. Recounting that experience, he reported that he was struck by the improvement in outcomes among patients who grasped that schizophrenia must be approached as a chronic disease.

“Once the patient understood what they had, they were much more apt to be adherent and to stay on their medication for their lifetime,” Dr. Glick reported. Although there is evidence that identifying an effective antipsychotic is key to disease control, “you have to talk to the patient, not just throw a medicine at them,” he said. This makes educating patients and families the key step in embarking on indefinite, close disease monitoring.

Control of schizophrenia over time is likely to vary as symptoms wax and wane, but this is true of other chronic disease processes. Diabetes, for example, requires frequent monitoring for and adjustment of blood glucose. Often medications for diabetes must be intensified or switched. The monitoring and management of schizophrenia is analogous.

One strategy for improving control of schizophrenia is to educate patients about this concept. Approaching schizophrenia as a chronic illness like other diseases that require lifetime drugs will help reduce the crises and the adverse effects associated with nonadherence to tight management, Dr. Glick maintained.

Dr. Glick reported financial relationships with Forum Pharmaceuticals, Johnson & Johnson, Neurocrine, Sunovion, and Teva.

TAMPA – The secret to optimal long-term disease control in schizophrenia is to implement the same type of continuous and close management provided to other chronic diseases, like hypertension or inflammatory bowel disease, according to a lecture delivered at the annual meeting of the American College of Psychiatrists.

In the Dean Award Lecture – a talk characterized as “a stroll through the long-term understanding of the treatment of schizophrenia” – Ira D. Glick, MD, said that, although antipsychotics provide the foundation of disease control, patients and families need to understand and respect disease chronicity.

“What I found in a relatively large sample was that the more adherent patients were to their medication, the more likely they were to report adequate satisfaction with their life,” Dr. Glick said. For those who were not adherent, life in general “has been a disaster.”

This finding is not entirely surprising given the power of antipsychotics to change thinking. However, for those engaged in the immediate task of controlling acute symptoms, the importance of chronicity might not be given adequate emphasis. This requires educating patients and their families about the need to embark on lifetime treatment, Dr. Glick said. Like a diagnosis of diabetes, a diagnosis of schizophrenia means constant vigilance for manifestations of disease and appropriate adjustments of therapy to improve long-term outcomes.

Since evaluating the relationship between medication adherence and long-term outcomes in patients with schizophrenia treated at Stanford, the same type of evaluation was conducted with population samples from the Veterans Affairs system and from China. The data “show exactly the same thing,” Dr. Glick said.

It is important to use every available resource in helping patients recognize and deal with schizophrenia chronicity. In addition to engaging families, he believes that organizations such as the National Alliance on Mental Illness or NAMI, are useful sources of support.

Earlier in his career, Dr. Glick participated in a randomized clinical trial of hospitalization for patients with schizophrenia. Recounting that experience, he reported that he was struck by the improvement in outcomes among patients who grasped that schizophrenia must be approached as a chronic disease.

“Once the patient understood what they had, they were much more apt to be adherent and to stay on their medication for their lifetime,” Dr. Glick reported. Although there is evidence that identifying an effective antipsychotic is key to disease control, “you have to talk to the patient, not just throw a medicine at them,” he said. This makes educating patients and families the key step in embarking on indefinite, close disease monitoring.

Control of schizophrenia over time is likely to vary as symptoms wax and wane, but this is true of other chronic disease processes. Diabetes, for example, requires frequent monitoring for and adjustment of blood glucose. Often medications for diabetes must be intensified or switched. The monitoring and management of schizophrenia is analogous.

One strategy for improving control of schizophrenia is to educate patients about this concept. Approaching schizophrenia as a chronic illness like other diseases that require lifetime drugs will help reduce the crises and the adverse effects associated with nonadherence to tight management, Dr. Glick maintained.

Dr. Glick reported financial relationships with Forum Pharmaceuticals, Johnson & Johnson, Neurocrine, Sunovion, and Teva.

TAMPA – The secret to optimal long-term disease control in schizophrenia is to implement the same type of continuous and close management provided to other chronic diseases, like hypertension or inflammatory bowel disease, according to a lecture delivered at the annual meeting of the American College of Psychiatrists.

In the Dean Award Lecture – a talk characterized as “a stroll through the long-term understanding of the treatment of schizophrenia” – Ira D. Glick, MD, said that, although antipsychotics provide the foundation of disease control, patients and families need to understand and respect disease chronicity.

“What I found in a relatively large sample was that the more adherent patients were to their medication, the more likely they were to report adequate satisfaction with their life,” Dr. Glick said. For those who were not adherent, life in general “has been a disaster.”

This finding is not entirely surprising given the power of antipsychotics to change thinking. However, for those engaged in the immediate task of controlling acute symptoms, the importance of chronicity might not be given adequate emphasis. This requires educating patients and their families about the need to embark on lifetime treatment, Dr. Glick said. Like a diagnosis of diabetes, a diagnosis of schizophrenia means constant vigilance for manifestations of disease and appropriate adjustments of therapy to improve long-term outcomes.

Since evaluating the relationship between medication adherence and long-term outcomes in patients with schizophrenia treated at Stanford, the same type of evaluation was conducted with population samples from the Veterans Affairs system and from China. The data “show exactly the same thing,” Dr. Glick said.

It is important to use every available resource in helping patients recognize and deal with schizophrenia chronicity. In addition to engaging families, he believes that organizations such as the National Alliance on Mental Illness or NAMI, are useful sources of support.

Earlier in his career, Dr. Glick participated in a randomized clinical trial of hospitalization for patients with schizophrenia. Recounting that experience, he reported that he was struck by the improvement in outcomes among patients who grasped that schizophrenia must be approached as a chronic disease.

“Once the patient understood what they had, they were much more apt to be adherent and to stay on their medication for their lifetime,” Dr. Glick reported. Although there is evidence that identifying an effective antipsychotic is key to disease control, “you have to talk to the patient, not just throw a medicine at them,” he said. This makes educating patients and families the key step in embarking on indefinite, close disease monitoring.

Control of schizophrenia over time is likely to vary as symptoms wax and wane, but this is true of other chronic disease processes. Diabetes, for example, requires frequent monitoring for and adjustment of blood glucose. Often medications for diabetes must be intensified or switched. The monitoring and management of schizophrenia is analogous.

One strategy for improving control of schizophrenia is to educate patients about this concept. Approaching schizophrenia as a chronic illness like other diseases that require lifetime drugs will help reduce the crises and the adverse effects associated with nonadherence to tight management, Dr. Glick maintained.

Dr. Glick reported financial relationships with Forum Pharmaceuticals, Johnson & Johnson, Neurocrine, Sunovion, and Teva.

A systematic review of 33 studies evaluating nonpharmacological treatments for acne provided what was described as “circumstantial” evidence of efficacy by the authors who conducted the analysis.

The 33 studies evaluated three types of treatments: laser-based and light-based treatments (20), chemical peels (11), and fractional microneedling radiofrequency (2); most were associated with significant reductions in acne lesions in the studies. The evidence for efficacy was “strong” for glycolic acid at concentrations from 10% to 40%, and “moderate” for amino fruit acids at concentrations of 20%-60%, for intense pulsed light (IPL: 400-700 and 870-1,200 nm), and for the diode laser 1450 nm, according to F.M.C. de Vries, MD, of the department of dermatology, Radboud University, Nijmegen, the Netherlands, and coauthors.

However, they added, “although a high rate of statistically significant results was found in most of the studies, indicating efficacy of nonpharmacological therapies, the low methodological quality of the included studies made it difficult to draw clear conclusions.” Most of the studies were limited by factors that included a small number of enrolled participants, short follow-up, and lack of or possibly inadequate blinding in participants and/or clinicians.

Their review of three electronic databases (MEDLINE, Cochrane library, CINAHL) identified the 33 studies evaluating these treatments in 1,404 participants with acne, published between January 2000 and May 2017, which met their inclusion criteria.

Most of the studies on laser- and light-based treatments found a “significant reduction in acne lesions,” including eight that had a control group. However, with two exceptions, “suboptimal methodologic quality of the majority of these studies resulted in limited evidence of efficacy,” they added. The exceptions were two studies that were the basis of their “moderate” rating for IPL and the diode laser: a randomized study of IPL (40-700 and 870-1,200 nm, 100 ms, 20 J/cm², 20 ms, 18 J/cm²), which found that treatment with IPL resulted in a significant reduction in papules, pustules, and comedones, compared with controls; and a randomized controlled study that found that treatment with a diode laser (1,450 nm, 9.5-11.0 J/cm², 29-30 ms) resulted in reductions in inflammatory acne that were statistically significant.

The review provided “circumstantial evidence for nonpharmacological therapies in the treatment of acne vulgaris” and “has created order and structure in resulting outcomes in which a first step towards future research is generated,” the authors concluded. “The large amount of studies performed in the area of acne treatment and the frequent application of these therapies in daily practice indicates a great interest in this topic and the urgent demand for effective nonpharmacological treatment options for acne in addition to the use of conventional therapies,” they added.

The authors had no disclosures. Of the six authors, Dr. de Vries and three other authors are affiliated with HU University of Applied Sciences, Utrecht, the Netherlands, which funded the study.

[email protected]

SOURCE: de Vries FMC et al. J Eur Acad Dermatol Venereol. 2018 Feb 14. doi: 10.1111/jdv.14881.

A systematic review of 33 studies evaluating nonpharmacological treatments for acne provided what was described as “circumstantial” evidence of efficacy by the authors who conducted the analysis.

The 33 studies evaluated three types of treatments: laser-based and light-based treatments (20), chemical peels (11), and fractional microneedling radiofrequency (2); most were associated with significant reductions in acne lesions in the studies. The evidence for efficacy was “strong” for glycolic acid at concentrations from 10% to 40%, and “moderate” for amino fruit acids at concentrations of 20%-60%, for intense pulsed light (IPL: 400-700 and 870-1,200 nm), and for the diode laser 1450 nm, according to F.M.C. de Vries, MD, of the department of dermatology, Radboud University, Nijmegen, the Netherlands, and coauthors.

However, they added, “although a high rate of statistically significant results was found in most of the studies, indicating efficacy of nonpharmacological therapies, the low methodological quality of the included studies made it difficult to draw clear conclusions.” Most of the studies were limited by factors that included a small number of enrolled participants, short follow-up, and lack of or possibly inadequate blinding in participants and/or clinicians.

Their review of three electronic databases (MEDLINE, Cochrane library, CINAHL) identified the 33 studies evaluating these treatments in 1,404 participants with acne, published between January 2000 and May 2017, which met their inclusion criteria.

Most of the studies on laser- and light-based treatments found a “significant reduction in acne lesions,” including eight that had a control group. However, with two exceptions, “suboptimal methodologic quality of the majority of these studies resulted in limited evidence of efficacy,” they added. The exceptions were two studies that were the basis of their “moderate” rating for IPL and the diode laser: a randomized study of IPL (40-700 and 870-1,200 nm, 100 ms, 20 J/cm², 20 ms, 18 J/cm²), which found that treatment with IPL resulted in a significant reduction in papules, pustules, and comedones, compared with controls; and a randomized controlled study that found that treatment with a diode laser (1,450 nm, 9.5-11.0 J/cm², 29-30 ms) resulted in reductions in inflammatory acne that were statistically significant.

The review provided “circumstantial evidence for nonpharmacological therapies in the treatment of acne vulgaris” and “has created order and structure in resulting outcomes in which a first step towards future research is generated,” the authors concluded. “The large amount of studies performed in the area of acne treatment and the frequent application of these therapies in daily practice indicates a great interest in this topic and the urgent demand for effective nonpharmacological treatment options for acne in addition to the use of conventional therapies,” they added.

The authors had no disclosures. Of the six authors, Dr. de Vries and three other authors are affiliated with HU University of Applied Sciences, Utrecht, the Netherlands, which funded the study.

[email protected]

SOURCE: de Vries FMC et al. J Eur Acad Dermatol Venereol. 2018 Feb 14. doi: 10.1111/jdv.14881.

A systematic review of 33 studies evaluating nonpharmacological treatments for acne provided what was described as “circumstantial” evidence of efficacy by the authors who conducted the analysis.

The 33 studies evaluated three types of treatments: laser-based and light-based treatments (20), chemical peels (11), and fractional microneedling radiofrequency (2); most were associated with significant reductions in acne lesions in the studies. The evidence for efficacy was “strong” for glycolic acid at concentrations from 10% to 40%, and “moderate” for amino fruit acids at concentrations of 20%-60%, for intense pulsed light (IPL: 400-700 and 870-1,200 nm), and for the diode laser 1450 nm, according to F.M.C. de Vries, MD, of the department of dermatology, Radboud University, Nijmegen, the Netherlands, and coauthors.

However, they added, “although a high rate of statistically significant results was found in most of the studies, indicating efficacy of nonpharmacological therapies, the low methodological quality of the included studies made it difficult to draw clear conclusions.” Most of the studies were limited by factors that included a small number of enrolled participants, short follow-up, and lack of or possibly inadequate blinding in participants and/or clinicians.

Their review of three electronic databases (MEDLINE, Cochrane library, CINAHL) identified the 33 studies evaluating these treatments in 1,404 participants with acne, published between January 2000 and May 2017, which met their inclusion criteria.

Most of the studies on laser- and light-based treatments found a “significant reduction in acne lesions,” including eight that had a control group. However, with two exceptions, “suboptimal methodologic quality of the majority of these studies resulted in limited evidence of efficacy,” they added. The exceptions were two studies that were the basis of their “moderate” rating for IPL and the diode laser: a randomized study of IPL (40-700 and 870-1,200 nm, 100 ms, 20 J/cm², 20 ms, 18 J/cm²), which found that treatment with IPL resulted in a significant reduction in papules, pustules, and comedones, compared with controls; and a randomized controlled study that found that treatment with a diode laser (1,450 nm, 9.5-11.0 J/cm², 29-30 ms) resulted in reductions in inflammatory acne that were statistically significant.

The review provided “circumstantial evidence for nonpharmacological therapies in the treatment of acne vulgaris” and “has created order and structure in resulting outcomes in which a first step towards future research is generated,” the authors concluded. “The large amount of studies performed in the area of acne treatment and the frequent application of these therapies in daily practice indicates a great interest in this topic and the urgent demand for effective nonpharmacological treatment options for acne in addition to the use of conventional therapies,” they added.

The authors had no disclosures. Of the six authors, Dr. de Vries and three other authors are affiliated with HU University of Applied Sciences, Utrecht, the Netherlands, which funded the study.

[email protected]

SOURCE: de Vries FMC et al. J Eur Acad Dermatol Venereol. 2018 Feb 14. doi: 10.1111/jdv.14881.

ORLANDO – Climate change is not just eroding coastlines and threatening seaside cities and taking lives with increasingly powerful hurricanes, but appears to be contributing to increases in allergy and asthma, an expert told the audience at the joint congress of the American Academy of Allergy, Asthma and Immunology and the World Asthma Organization.

Longer pollen seasons, allergens unleashed by felled trees and ripped-up plants, mold growth following floods, and irritants launched into the air by wildfires are some of the concerns that should be alarming physicians and policy makers, said Nelson A. Rosario, MD, PhD, professor of pediatrics at Federal University of Paraná (Brazil).

Thomas R. Collins/Frontline Medical Communications

Gilitukha/Thinkstock

[email protected]

ORLANDO – Climate change is not just eroding coastlines and threatening seaside cities and taking lives with increasingly powerful hurricanes, but appears to be contributing to increases in allergy and asthma, an expert told the audience at the joint congress of the American Academy of Allergy, Asthma and Immunology and the World Asthma Organization.

Longer pollen seasons, allergens unleashed by felled trees and ripped-up plants, mold growth following floods, and irritants launched into the air by wildfires are some of the concerns that should be alarming physicians and policy makers, said Nelson A. Rosario, MD, PhD, professor of pediatrics at Federal University of Paraná (Brazil).

Thomas R. Collins/Frontline Medical Communications

Gilitukha/Thinkstock

[email protected]

ORLANDO – Climate change is not just eroding coastlines and threatening seaside cities and taking lives with increasingly powerful hurricanes, but appears to be contributing to increases in allergy and asthma, an expert told the audience at the joint congress of the American Academy of Allergy, Asthma and Immunology and the World Asthma Organization.

Longer pollen seasons, allergens unleashed by felled trees and ripped-up plants, mold growth following floods, and irritants launched into the air by wildfires are some of the concerns that should be alarming physicians and policy makers, said Nelson A. Rosario, MD, PhD, professor of pediatrics at Federal University of Paraná (Brazil).

Thomas R. Collins/Frontline Medical Communications

Gilitukha/Thinkstock

[email protected]

ATLANTA – Mitoxantrone, etoposide, and cytarabine (MEC) in combination with the second-generation proteasome inhibitor ixazomib was well tolerated and effective in a phase 1 expansion study of patients with relapsed or refractory acute myeloid leukemia.

The overall response rate in 30 patients enrolled in the study and treated with the novel combination was 53%; 11 patients had a complete response (CR), and 5 had a complete response with incomplete blood count recovery (CRi). The median overall survival was 4.9 months, Anjali S. Advani, MD, reported at the annual meeting of the American Society of Hematology.

Thirteen patients proceeded to allogeneic hematopoietic cell transplant (AHCT), and one received a donor lymphocyte infusion. Seven of these 14 patients are alive with a median follow-up of 14.5 months, said Dr. Advani of Taussig Cancer Institute, Cleveland Clinic.

The patients, who had a median age of 58 years (range of 18-70 years), were eligible for the study if they had relapsed/refractory acute myeloid leukemia (AML), adequate organ function, and cardiac ejection fraction of at least 45%. The median time from initial diagnosis to enrollment was 7.6 months.

[email protected]

ATLANTA – Mitoxantrone, etoposide, and cytarabine (MEC) in combination with the second-generation proteasome inhibitor ixazomib was well tolerated and effective in a phase 1 expansion study of patients with relapsed or refractory acute myeloid leukemia.

The overall response rate in 30 patients enrolled in the study and treated with the novel combination was 53%; 11 patients had a complete response (CR), and 5 had a complete response with incomplete blood count recovery (CRi). The median overall survival was 4.9 months, Anjali S. Advani, MD, reported at the annual meeting of the American Society of Hematology.

Thirteen patients proceeded to allogeneic hematopoietic cell transplant (AHCT), and one received a donor lymphocyte infusion. Seven of these 14 patients are alive with a median follow-up of 14.5 months, said Dr. Advani of Taussig Cancer Institute, Cleveland Clinic.

The patients, who had a median age of 58 years (range of 18-70 years), were eligible for the study if they had relapsed/refractory acute myeloid leukemia (AML), adequate organ function, and cardiac ejection fraction of at least 45%. The median time from initial diagnosis to enrollment was 7.6 months.

[email protected]

ATLANTA – Mitoxantrone, etoposide, and cytarabine (MEC) in combination with the second-generation proteasome inhibitor ixazomib was well tolerated and effective in a phase 1 expansion study of patients with relapsed or refractory acute myeloid leukemia.

The overall response rate in 30 patients enrolled in the study and treated with the novel combination was 53%; 11 patients had a complete response (CR), and 5 had a complete response with incomplete blood count recovery (CRi). The median overall survival was 4.9 months, Anjali S. Advani, MD, reported at the annual meeting of the American Society of Hematology.

Thirteen patients proceeded to allogeneic hematopoietic cell transplant (AHCT), and one received a donor lymphocyte infusion. Seven of these 14 patients are alive with a median follow-up of 14.5 months, said Dr. Advani of Taussig Cancer Institute, Cleveland Clinic.

The patients, who had a median age of 58 years (range of 18-70 years), were eligible for the study if they had relapsed/refractory acute myeloid leukemia (AML), adequate organ function, and cardiac ejection fraction of at least 45%. The median time from initial diagnosis to enrollment was 7.6 months.

[email protected]

This is the seventh in a series of articles from the National Center for Excellence in Primary Care Research (NCEPCR) in the Agency for Healthcare Research and Quality (AHRQ). This series introduces sets of tools and resources designed to help your practice.

Thus far, this series has discussed topics such as shared decision making, team-based care, and integrating behavioral health and primary care. All of these are important topics, but this raises the question, “How do I make the changes to my practice?” This month’s article discusses AHRQ’s resources for transforming your practice to be able to better introduce these advances.

Care coordination. The main goal of care coordination is to meet patients’ needs and preferences in the delivery of high-quality, high-value health care. This means that the patient’s needs and preferences are known and communicated at the right time to the right people, which results in safe, appropriate, and effective care. AHRQ’s resources in this area offer examples of care coordination approaches and activities, as well as guidance and models for understanding and measuring patients’ perceptions of care coordination.

Improvement approaches related to patient engagement and support. Several different types of resources related to patient engagement are available. These include the what, why, and how of self-management support, implementing health literacy universal precautions, and engaging patients and families in patient safety efforts.

AHRQ’s Primary Care YouTube channel offers videos from clinical staff, researchers, and others describing their work in many of these areas.

While the goal of practice transformation is the improvement of patient care and patient outcomes, patient and staff satisfaction (including issues regarding provider burnout) must not be lost in the process. The Clinician & Group Survey of the Consumer Assessment of Healthcare Providers and Systems assesses patient experiences with health care providers and staff in doctors’ offices. Survey results can be used to improve care provided by individual providers, sites of care, medical groups, or provider networks, as well as equip consumers with information they can use to choose physicians and other health care providers, physician practices, or medical groups. The survey includes standardized questionnaires for adults and children. The adult questionnaire can be used in both primary care and specialty care settings; the child questionnaire is designed for primary care settings but could be adapted for specialty care. Users can also add supplemental items to customize their questionnaires.

For many practices, working with a practice facilitator will be a big part of the transformation. Practice facilitation is an evidence-based approach to quality improvement in primary care practices. It will be discussed at length next month. In addition, in July and August, we will discuss optimizing health information technology and workflow in your practice.

Dr. Genevro is a health scientist at AHRQ. Dr. Ganiats is the director of the National Center for Excellence in Primary Care Research at AHRQ.

This is the seventh in a series of articles from the National Center for Excellence in Primary Care Research (NCEPCR) in the Agency for Healthcare Research and Quality (AHRQ). This series introduces sets of tools and resources designed to help your practice.

Thus far, this series has discussed topics such as shared decision making, team-based care, and integrating behavioral health and primary care. All of these are important topics, but this raises the question, “How do I make the changes to my practice?” This month’s article discusses AHRQ’s resources for transforming your practice to be able to better introduce these advances.

Care coordination. The main goal of care coordination is to meet patients’ needs and preferences in the delivery of high-quality, high-value health care. This means that the patient’s needs and preferences are known and communicated at the right time to the right people, which results in safe, appropriate, and effective care. AHRQ’s resources in this area offer examples of care coordination approaches and activities, as well as guidance and models for understanding and measuring patients’ perceptions of care coordination.

Improvement approaches related to patient engagement and support. Several different types of resources related to patient engagement are available. These include the what, why, and how of self-management support, implementing health literacy universal precautions, and engaging patients and families in patient safety efforts.

AHRQ’s Primary Care YouTube channel offers videos from clinical staff, researchers, and others describing their work in many of these areas.

While the goal of practice transformation is the improvement of patient care and patient outcomes, patient and staff satisfaction (including issues regarding provider burnout) must not be lost in the process. The Clinician & Group Survey of the Consumer Assessment of Healthcare Providers and Systems assesses patient experiences with health care providers and staff in doctors’ offices. Survey results can be used to improve care provided by individual providers, sites of care, medical groups, or provider networks, as well as equip consumers with information they can use to choose physicians and other health care providers, physician practices, or medical groups. The survey includes standardized questionnaires for adults and children. The adult questionnaire can be used in both primary care and specialty care settings; the child questionnaire is designed for primary care settings but could be adapted for specialty care. Users can also add supplemental items to customize their questionnaires.

For many practices, working with a practice facilitator will be a big part of the transformation. Practice facilitation is an evidence-based approach to quality improvement in primary care practices. It will be discussed at length next month. In addition, in July and August, we will discuss optimizing health information technology and workflow in your practice.

Dr. Genevro is a health scientist at AHRQ. Dr. Ganiats is the director of the National Center for Excellence in Primary Care Research at AHRQ.

This is the seventh in a series of articles from the National Center for Excellence in Primary Care Research (NCEPCR) in the Agency for Healthcare Research and Quality (AHRQ). This series introduces sets of tools and resources designed to help your practice.

Thus far, this series has discussed topics such as shared decision making, team-based care, and integrating behavioral health and primary care. All of these are important topics, but this raises the question, “How do I make the changes to my practice?” This month’s article discusses AHRQ’s resources for transforming your practice to be able to better introduce these advances.

Care coordination. The main goal of care coordination is to meet patients’ needs and preferences in the delivery of high-quality, high-value health care. This means that the patient’s needs and preferences are known and communicated at the right time to the right people, which results in safe, appropriate, and effective care. AHRQ’s resources in this area offer examples of care coordination approaches and activities, as well as guidance and models for understanding and measuring patients’ perceptions of care coordination.

Improvement approaches related to patient engagement and support. Several different types of resources related to patient engagement are available. These include the what, why, and how of self-management support, implementing health literacy universal precautions, and engaging patients and families in patient safety efforts.

AHRQ’s Primary Care YouTube channel offers videos from clinical staff, researchers, and others describing their work in many of these areas.

While the goal of practice transformation is the improvement of patient care and patient outcomes, patient and staff satisfaction (including issues regarding provider burnout) must not be lost in the process. The Clinician & Group Survey of the Consumer Assessment of Healthcare Providers and Systems assesses patient experiences with health care providers and staff in doctors’ offices. Survey results can be used to improve care provided by individual providers, sites of care, medical groups, or provider networks, as well as equip consumers with information they can use to choose physicians and other health care providers, physician practices, or medical groups. The survey includes standardized questionnaires for adults and children. The adult questionnaire can be used in both primary care and specialty care settings; the child questionnaire is designed for primary care settings but could be adapted for specialty care. Users can also add supplemental items to customize their questionnaires.

For many practices, working with a practice facilitator will be a big part of the transformation. Practice facilitation is an evidence-based approach to quality improvement in primary care practices. It will be discussed at length next month. In addition, in July and August, we will discuss optimizing health information technology and workflow in your practice.

Dr. Genevro is a health scientist at AHRQ. Dr. Ganiats is the director of the National Center for Excellence in Primary Care Research at AHRQ.

SILVER SPRING, MD. – Federal advisors to the Food and Drug Administration on March 8 voted unanimously to recommend approval of an additional indication for tofacitinib (Xeljanz), this time for ulcerative colitis.

Members of the Gastrointestinal Drugs Advisory Committee unanimously voted to recommend two different dosing regimens: 10 mg twice daily for 16 weeks in patients who have not experienced a therapeutic benefit after 8 weeks of treatment, as well as 10 mg twice daily for patients who have an inadequate or loss of response to TNF-blocker therapy, based on the results of several phase 3 clinical trials.

The induction trials enrolled a total of 1,139 patients with moderate to severe UC. Patients in both studies were administered tofacitinib 10 mg twice daily or placebo and were assessed after 8 weeks to judge clinical response. Patients in both studies displayed notable remission rates (18.5% and 16.6%), compared with placebo, according to Eric Maller, MD, executive director of the UC development program at Pfizer.*

Patients who did not achieve remission, but showed some clinical response (decrease in Mayo score of at least 3 points), were then enrolled in the 53-week OCTAVE Sustain, where they were randomized to receive tofacitinib 10 mg twice daily, 5 mg twice daily, or placebo.

During maintenance treatment, both 5 mg and 10 mg doses demonstrated substantial treatment benefits, with 32.4% and 41.0% of patients achieving remission, an increase of 22.0% and 30.7%, compared with placebo, respectively.

As part of the maintenance study, Pfizer analyzed patients with or without prior TNF-blocker failure. This analysis revealed that patients who had previously failed TNF-blocker therapy experienced a greater treatment benefit than those who had not. While the benefit was noticeable in both dosage groups, patients taking the 10-mg dose experienced the greatest benefit, with 70% increase in remission rates, 39% increase in mucosal healing, and 75% increase in steroid-free remission among baseline remitters, compared with patients in the 5-mg group, Dr. Maller said.

Researchers also looked at a subgroup of 295 patients as part of an open-label extension study who had no clinical response to tofacitinib 10 mg twice daily after 8 weeks and subsequently treated them for an additional 8 weeks. After the additional 8 weeks of treatment, over half (51.2%) displayed clinical responses and 8.6% were in remission.

“This is a desperate patient population. These are impressive results,” stated Darrell Pardi, MD, vice chair of the advisory committee and professor of medicine at the Mayo Clinic, Rochester, Minn.

Serious adverse events were seen in 4% of tofacitinib-treated patients in the induction trials, compared with 6% of placebo-treated, according to Lesley Hanes, MD, medical officer with the FDA Center for Drug Evaluation and Research.

Adverse events appeared to be dose dependent, with risk of deaths and malignancies (excluding nonmelanoma skin cancer), opportunistic infections, herpes zoster infection (HZ), “possible” drug-induced liver injury, and cardiovascular and thromboembolic events more common with the 10-mg dose, Dr. Hanes said.*

“I think the safety concerns, though, they are dose dependent, the difference between the 5 [mg] and 10 [mg] were not large,” according to Dr. Pardi. “Several of these are mitigatable by dermatologic exam or, hopefully, a vaccine.”

Several of the advisory committee members submitted conflict of interest waivers. Chair and vice chair Jean-Pierre Raufman, MD, and Darrell Pardi, MD, disclosed funding from competing pharmaceutical manufacturers.

*This article was updated on March 12, 2018.

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SILVER SPRING, MD. – Federal advisors to the Food and Drug Administration on March 8 voted unanimously to recommend approval of an additional indication for tofacitinib (Xeljanz), this time for ulcerative colitis.

Members of the Gastrointestinal Drugs Advisory Committee unanimously voted to recommend two different dosing regimens: 10 mg twice daily for 16 weeks in patients who have not experienced a therapeutic benefit after 8 weeks of treatment, as well as 10 mg twice daily for patients who have an inadequate or loss of response to TNF-blocker therapy, based on the results of several phase 3 clinical trials.

The induction trials enrolled a total of 1,139 patients with moderate to severe UC. Patients in both studies were administered tofacitinib 10 mg twice daily or placebo and were assessed after 8 weeks to judge clinical response. Patients in both studies displayed notable remission rates (18.5% and 16.6%), compared with placebo, according to Eric Maller, MD, executive director of the UC development program at Pfizer.*

Patients who did not achieve remission, but showed some clinical response (decrease in Mayo score of at least 3 points), were then enrolled in the 53-week OCTAVE Sustain, where they were randomized to receive tofacitinib 10 mg twice daily, 5 mg twice daily, or placebo.

During maintenance treatment, both 5 mg and 10 mg doses demonstrated substantial treatment benefits, with 32.4% and 41.0% of patients achieving remission, an increase of 22.0% and 30.7%, compared with placebo, respectively.

As part of the maintenance study, Pfizer analyzed patients with or without prior TNF-blocker failure. This analysis revealed that patients who had previously failed TNF-blocker therapy experienced a greater treatment benefit than those who had not. While the benefit was noticeable in both dosage groups, patients taking the 10-mg dose experienced the greatest benefit, with 70% increase in remission rates, 39% increase in mucosal healing, and 75% increase in steroid-free remission among baseline remitters, compared with patients in the 5-mg group, Dr. Maller said.

Researchers also looked at a subgroup of 295 patients as part of an open-label extension study who had no clinical response to tofacitinib 10 mg twice daily after 8 weeks and subsequently treated them for an additional 8 weeks. After the additional 8 weeks of treatment, over half (51.2%) displayed clinical responses and 8.6% were in remission.

“This is a desperate patient population. These are impressive results,” stated Darrell Pardi, MD, vice chair of the advisory committee and professor of medicine at the Mayo Clinic, Rochester, Minn.

Serious adverse events were seen in 4% of tofacitinib-treated patients in the induction trials, compared with 6% of placebo-treated, according to Lesley Hanes, MD, medical officer with the FDA Center for Drug Evaluation and Research.

Adverse events appeared to be dose dependent, with risk of deaths and malignancies (excluding nonmelanoma skin cancer), opportunistic infections, herpes zoster infection (HZ), “possible” drug-induced liver injury, and cardiovascular and thromboembolic events more common with the 10-mg dose, Dr. Hanes said.*

“I think the safety concerns, though, they are dose dependent, the difference between the 5 [mg] and 10 [mg] were not large,” according to Dr. Pardi. “Several of these are mitigatable by dermatologic exam or, hopefully, a vaccine.”

Several of the advisory committee members submitted conflict of interest waivers. Chair and vice chair Jean-Pierre Raufman, MD, and Darrell Pardi, MD, disclosed funding from competing pharmaceutical manufacturers.

*This article was updated on March 12, 2018.

[email protected]

SILVER SPRING, MD. – Federal advisors to the Food and Drug Administration on March 8 voted unanimously to recommend approval of an additional indication for tofacitinib (Xeljanz), this time for ulcerative colitis.

Members of the Gastrointestinal Drugs Advisory Committee unanimously voted to recommend two different dosing regimens: 10 mg twice daily for 16 weeks in patients who have not experienced a therapeutic benefit after 8 weeks of treatment, as well as 10 mg twice daily for patients who have an inadequate or loss of response to TNF-blocker therapy, based on the results of several phase 3 clinical trials.

The induction trials enrolled a total of 1,139 patients with moderate to severe UC. Patients in both studies were administered tofacitinib 10 mg twice daily or placebo and were assessed after 8 weeks to judge clinical response. Patients in both studies displayed notable remission rates (18.5% and 16.6%), compared with placebo, according to Eric Maller, MD, executive director of the UC development program at Pfizer.*

Patients who did not achieve remission, but showed some clinical response (decrease in Mayo score of at least 3 points), were then enrolled in the 53-week OCTAVE Sustain, where they were randomized to receive tofacitinib 10 mg twice daily, 5 mg twice daily, or placebo.

During maintenance treatment, both 5 mg and 10 mg doses demonstrated substantial treatment benefits, with 32.4% and 41.0% of patients achieving remission, an increase of 22.0% and 30.7%, compared with placebo, respectively.

As part of the maintenance study, Pfizer analyzed patients with or without prior TNF-blocker failure. This analysis revealed that patients who had previously failed TNF-blocker therapy experienced a greater treatment benefit than those who had not. While the benefit was noticeable in both dosage groups, patients taking the 10-mg dose experienced the greatest benefit, with 70% increase in remission rates, 39% increase in mucosal healing, and 75% increase in steroid-free remission among baseline remitters, compared with patients in the 5-mg group, Dr. Maller said.

Researchers also looked at a subgroup of 295 patients as part of an open-label extension study who had no clinical response to tofacitinib 10 mg twice daily after 8 weeks and subsequently treated them for an additional 8 weeks. After the additional 8 weeks of treatment, over half (51.2%) displayed clinical responses and 8.6% were in remission.

“This is a desperate patient population. These are impressive results,” stated Darrell Pardi, MD, vice chair of the advisory committee and professor of medicine at the Mayo Clinic, Rochester, Minn.

Serious adverse events were seen in 4% of tofacitinib-treated patients in the induction trials, compared with 6% of placebo-treated, according to Lesley Hanes, MD, medical officer with the FDA Center for Drug Evaluation and Research.

Adverse events appeared to be dose dependent, with risk of deaths and malignancies (excluding nonmelanoma skin cancer), opportunistic infections, herpes zoster infection (HZ), “possible” drug-induced liver injury, and cardiovascular and thromboembolic events more common with the 10-mg dose, Dr. Hanes said.*

“I think the safety concerns, though, they are dose dependent, the difference between the 5 [mg] and 10 [mg] were not large,” according to Dr. Pardi. “Several of these are mitigatable by dermatologic exam or, hopefully, a vaccine.”

Several of the advisory committee members submitted conflict of interest waivers. Chair and vice chair Jean-Pierre Raufman, MD, and Darrell Pardi, MD, disclosed funding from competing pharmaceutical manufacturers.

*This article was updated on March 12, 2018.

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