What does your patient need to know at the first visit?

The most essential information to share with patients at the first visit (as well as at all subsequent visits) is your eczema action plan, which should include discussion and potential modification of bathing regimens, use of topical emollients and medications, and exposure to detergents. It also is important to discuss the patient’s disease pattern (eg, triggers, seasonal flares, other forms of atopy), medication history, and past treatment responses. The eczema action plan is extremely vital for a variety of reasons. As a physician, I can’t be present every time a patient has a severe flare, and it would be difficult—both physically and financially—for patients to come in to my office every time a flare occurs. Patients and their caregivers need to develop a sense of empowerment at the first visit so they can address symptoms as they arise and actively prevent severe flares by following a gentle skin care plan that includes topical emollients and gentle cleansing.

I also like to emphasize to my eczema patients that they are not alone. In the United States, almost one-quarter of the population may have eczema. It’s also essential to explain to patients/caregivers that eczema is not caused by food allergies and cannot be cured by food elimination or other dietary modifications. Finally, I like to explain to patients that there is no true cure for eczema and that they will need to follow the action plan throughout their lifetime to help treat and prevent flares. Follow-up visits to review therapeutic response and review the patient’s eczema action plan can reinforce adherence and knowledge about the disease.

What are your go-to treatments? Are there any side effects?

Typically I prescribe 3 to 4 medications, which include an agent for the head and neck areas and/or areas of sensitive or thin skin, an agent for the body, an antihistamine to address sleep disturbances, and a rescue medication, which is a somewhat stronger topical agent for severe areas if present. Elimination of triggers such as fragrance and wool can be discussed. Review of Staphylococcus aureus as a trigger and addressing this trigger with bleach baths or other modifications (eg, topical antibacterials for crusted areas of skin) is needed.

Eczema treatment is a multistep process that varies by individual as well as by cost. For most eczema patients, treatment typically costs hundreds of dollars per year; therefore, I try to be mindful of the financial hardship that can be brought on by the need for many products. The mainstay of eczema therapy includes topical emollients along with gentle cleansers, laundry detergents, and other topical products. Topical corticosteroids are the first-line treatment and have been used for over 60 years with good outcomes in most patients when used judiciously; however, side effects including striae, glaucoma and hypothalamic-pituitary-adrenal axis suppression can occur. Topical corticosteroids should be selected by class and formulation—ointments and some newer base formulations are known to cause the least amount of stinging. In infants, the least potent agent that clears the skin effectively may maximize outcomes and minimize risk for side effects. Topical calcineurin inhibitors may be a good option in patients who do not respond to corticosteroids and are supported by excellent clinical evidence; however, be sure to consider the black box warnings.^1-3 Sedating antihistamines can be prescribed for bedtime usage in pruritic patients who experience sleep disturbances.

How do you keep patients compliant with treatment?

Patients can only comply with treatment if they have an adequate supply of the treatment product. It is important to prescribe the right amount of product needed to treat the affected area. Provision of refills for recurrent disease also can ensure long-term treatment compliance.

It also is important to have a conversation with patients about the nature of their disease flares. In my practice, patients typically report having seasonal flares, especially in midsummer temperatures or when the indoor heating kicks on in late fall. Encourage patients to schedule appointments in advance of these seasons; refilling medications beforehand and liberal application of emollients also can mitigate seasonal flares.

Finally, I try to recommend or prescribe treatments that appeal to patients both physically and emotionally. Some patients have a fear of using topical corticosteroids (known as corticophobia or steroid phobia). For these patients, I maximize the use of topical emollients and/or enhanced emollients (eg, agents with lipid additives and ceramides) to reduce the need for topical corticosteroids. I also have found that many preteen boys dislike “sticky” emollients, so light or midweight creams may be more tolerable for nightly use in this population. Another common scenario is the patient who prefers natural products. There are a variety of natural agents available that can aid in the treatment of eczema, including coconut oil, ceramide-based products, and oleodistillates. I try to refer to the literature to encourage the use of natural products that are backed by good science rather than big hype.

What do you do if patients refuse treatment?

As a physician, I can’t force patients or their caregivers to adhere to the therapies I prescribe; however, most patients are genuinely seeking a better quality of life and therefore there usually is at least some aspect of a skin care regimen they will follow to achieve relief when needed. First I make sure that serious issues (eg, bacterial infections) are addressed. I do mention to patients/caregivers that lack of treatment with topical prescription agents may have biological consequences; for example, there is evidence to support the Atopic March (ie, progression of atopic diseases to food allergies, asthma, etc). Consequences also can include discomfort, reduced quality of life, and negative effects on personal relationships; pediatric patients also may be stigmatized by their peers. Exploration of the root cause of treatment refusal usually yields a helpful discussion with the patient/caregiver about their fears as well as alternative treatment agents. Sometimes I engage the pediatrician/primary care physician, an allergist, or a family member in the discussion to enhance compliance and provide patient/caregiver support. At the very least, most patients/caregivers will adhere to trigger avoidance and barrier repair through application of emollients.

What resources do you recommend to patients for more information?

There are many resources available to patients that may enhance the overall management of eczema. I give my patients an educational handout about eczema as well as a hardcopy of their personal eczema action plan. For pediatric patients, I write the child’s first name and the date to help his or her caregivers remember when they received the plan. Examples of eczema action plans can be found in published resources ranging from simple to complex regimens and should be tailored to the physician’s own patient education and treatment patterns.^4,5 The National Eczema Association Web site (https://nationaleczema.org/) provides many resources for patients, including educational tools and an online community.

What does your patient need to know at the first visit?

The most essential information to share with patients at the first visit (as well as at all subsequent visits) is your eczema action plan, which should include discussion and potential modification of bathing regimens, use of topical emollients and medications, and exposure to detergents. It also is important to discuss the patient’s disease pattern (eg, triggers, seasonal flares, other forms of atopy), medication history, and past treatment responses. The eczema action plan is extremely vital for a variety of reasons. As a physician, I can’t be present every time a patient has a severe flare, and it would be difficult—both physically and financially—for patients to come in to my office every time a flare occurs. Patients and their caregivers need to develop a sense of empowerment at the first visit so they can address symptoms as they arise and actively prevent severe flares by following a gentle skin care plan that includes topical emollients and gentle cleansing.

I also like to emphasize to my eczema patients that they are not alone. In the United States, almost one-quarter of the population may have eczema. It’s also essential to explain to patients/caregivers that eczema is not caused by food allergies and cannot be cured by food elimination or other dietary modifications. Finally, I like to explain to patients that there is no true cure for eczema and that they will need to follow the action plan throughout their lifetime to help treat and prevent flares. Follow-up visits to review therapeutic response and review the patient’s eczema action plan can reinforce adherence and knowledge about the disease.

What are your go-to treatments? Are there any side effects?

Typically I prescribe 3 to 4 medications, which include an agent for the head and neck areas and/or areas of sensitive or thin skin, an agent for the body, an antihistamine to address sleep disturbances, and a rescue medication, which is a somewhat stronger topical agent for severe areas if present. Elimination of triggers such as fragrance and wool can be discussed. Review of Staphylococcus aureus as a trigger and addressing this trigger with bleach baths or other modifications (eg, topical antibacterials for crusted areas of skin) is needed.

Eczema treatment is a multistep process that varies by individual as well as by cost. For most eczema patients, treatment typically costs hundreds of dollars per year; therefore, I try to be mindful of the financial hardship that can be brought on by the need for many products. The mainstay of eczema therapy includes topical emollients along with gentle cleansers, laundry detergents, and other topical products. Topical corticosteroids are the first-line treatment and have been used for over 60 years with good outcomes in most patients when used judiciously; however, side effects including striae, glaucoma and hypothalamic-pituitary-adrenal axis suppression can occur. Topical corticosteroids should be selected by class and formulation—ointments and some newer base formulations are known to cause the least amount of stinging. In infants, the least potent agent that clears the skin effectively may maximize outcomes and minimize risk for side effects. Topical calcineurin inhibitors may be a good option in patients who do not respond to corticosteroids and are supported by excellent clinical evidence; however, be sure to consider the black box warnings.^1-3 Sedating antihistamines can be prescribed for bedtime usage in pruritic patients who experience sleep disturbances.

How do you keep patients compliant with treatment?

Patients can only comply with treatment if they have an adequate supply of the treatment product. It is important to prescribe the right amount of product needed to treat the affected area. Provision of refills for recurrent disease also can ensure long-term treatment compliance.

It also is important to have a conversation with patients about the nature of their disease flares. In my practice, patients typically report having seasonal flares, especially in midsummer temperatures or when the indoor heating kicks on in late fall. Encourage patients to schedule appointments in advance of these seasons; refilling medications beforehand and liberal application of emollients also can mitigate seasonal flares.

Finally, I try to recommend or prescribe treatments that appeal to patients both physically and emotionally. Some patients have a fear of using topical corticosteroids (known as corticophobia or steroid phobia). For these patients, I maximize the use of topical emollients and/or enhanced emollients (eg, agents with lipid additives and ceramides) to reduce the need for topical corticosteroids. I also have found that many preteen boys dislike “sticky” emollients, so light or midweight creams may be more tolerable for nightly use in this population. Another common scenario is the patient who prefers natural products. There are a variety of natural agents available that can aid in the treatment of eczema, including coconut oil, ceramide-based products, and oleodistillates. I try to refer to the literature to encourage the use of natural products that are backed by good science rather than big hype.

What do you do if patients refuse treatment?

As a physician, I can’t force patients or their caregivers to adhere to the therapies I prescribe; however, most patients are genuinely seeking a better quality of life and therefore there usually is at least some aspect of a skin care regimen they will follow to achieve relief when needed. First I make sure that serious issues (eg, bacterial infections) are addressed. I do mention to patients/caregivers that lack of treatment with topical prescription agents may have biological consequences; for example, there is evidence to support the Atopic March (ie, progression of atopic diseases to food allergies, asthma, etc). Consequences also can include discomfort, reduced quality of life, and negative effects on personal relationships; pediatric patients also may be stigmatized by their peers. Exploration of the root cause of treatment refusal usually yields a helpful discussion with the patient/caregiver about their fears as well as alternative treatment agents. Sometimes I engage the pediatrician/primary care physician, an allergist, or a family member in the discussion to enhance compliance and provide patient/caregiver support. At the very least, most patients/caregivers will adhere to trigger avoidance and barrier repair through application of emollients.

What resources do you recommend to patients for more information?

There are many resources available to patients that may enhance the overall management of eczema. I give my patients an educational handout about eczema as well as a hardcopy of their personal eczema action plan. For pediatric patients, I write the child’s first name and the date to help his or her caregivers remember when they received the plan. Examples of eczema action plans can be found in published resources ranging from simple to complex regimens and should be tailored to the physician’s own patient education and treatment patterns.^4,5 The National Eczema Association Web site (https://nationaleczema.org/) provides many resources for patients, including educational tools and an online community.

What does your patient need to know at the first visit?

The most essential information to share with patients at the first visit (as well as at all subsequent visits) is your eczema action plan, which should include discussion and potential modification of bathing regimens, use of topical emollients and medications, and exposure to detergents. It also is important to discuss the patient’s disease pattern (eg, triggers, seasonal flares, other forms of atopy), medication history, and past treatment responses. The eczema action plan is extremely vital for a variety of reasons. As a physician, I can’t be present every time a patient has a severe flare, and it would be difficult—both physically and financially—for patients to come in to my office every time a flare occurs. Patients and their caregivers need to develop a sense of empowerment at the first visit so they can address symptoms as they arise and actively prevent severe flares by following a gentle skin care plan that includes topical emollients and gentle cleansing.

I also like to emphasize to my eczema patients that they are not alone. In the United States, almost one-quarter of the population may have eczema. It’s also essential to explain to patients/caregivers that eczema is not caused by food allergies and cannot be cured by food elimination or other dietary modifications. Finally, I like to explain to patients that there is no true cure for eczema and that they will need to follow the action plan throughout their lifetime to help treat and prevent flares. Follow-up visits to review therapeutic response and review the patient’s eczema action plan can reinforce adherence and knowledge about the disease.

What are your go-to treatments? Are there any side effects?

Typically I prescribe 3 to 4 medications, which include an agent for the head and neck areas and/or areas of sensitive or thin skin, an agent for the body, an antihistamine to address sleep disturbances, and a rescue medication, which is a somewhat stronger topical agent for severe areas if present. Elimination of triggers such as fragrance and wool can be discussed. Review of Staphylococcus aureus as a trigger and addressing this trigger with bleach baths or other modifications (eg, topical antibacterials for crusted areas of skin) is needed.

Eczema treatment is a multistep process that varies by individual as well as by cost. For most eczema patients, treatment typically costs hundreds of dollars per year; therefore, I try to be mindful of the financial hardship that can be brought on by the need for many products. The mainstay of eczema therapy includes topical emollients along with gentle cleansers, laundry detergents, and other topical products. Topical corticosteroids are the first-line treatment and have been used for over 60 years with good outcomes in most patients when used judiciously; however, side effects including striae, glaucoma and hypothalamic-pituitary-adrenal axis suppression can occur. Topical corticosteroids should be selected by class and formulation—ointments and some newer base formulations are known to cause the least amount of stinging. In infants, the least potent agent that clears the skin effectively may maximize outcomes and minimize risk for side effects. Topical calcineurin inhibitors may be a good option in patients who do not respond to corticosteroids and are supported by excellent clinical evidence; however, be sure to consider the black box warnings.^1-3 Sedating antihistamines can be prescribed for bedtime usage in pruritic patients who experience sleep disturbances.

How do you keep patients compliant with treatment?

Patients can only comply with treatment if they have an adequate supply of the treatment product. It is important to prescribe the right amount of product needed to treat the affected area. Provision of refills for recurrent disease also can ensure long-term treatment compliance.

It also is important to have a conversation with patients about the nature of their disease flares. In my practice, patients typically report having seasonal flares, especially in midsummer temperatures or when the indoor heating kicks on in late fall. Encourage patients to schedule appointments in advance of these seasons; refilling medications beforehand and liberal application of emollients also can mitigate seasonal flares.

Finally, I try to recommend or prescribe treatments that appeal to patients both physically and emotionally. Some patients have a fear of using topical corticosteroids (known as corticophobia or steroid phobia). For these patients, I maximize the use of topical emollients and/or enhanced emollients (eg, agents with lipid additives and ceramides) to reduce the need for topical corticosteroids. I also have found that many preteen boys dislike “sticky” emollients, so light or midweight creams may be more tolerable for nightly use in this population. Another common scenario is the patient who prefers natural products. There are a variety of natural agents available that can aid in the treatment of eczema, including coconut oil, ceramide-based products, and oleodistillates. I try to refer to the literature to encourage the use of natural products that are backed by good science rather than big hype.

What do you do if patients refuse treatment?

As a physician, I can’t force patients or their caregivers to adhere to the therapies I prescribe; however, most patients are genuinely seeking a better quality of life and therefore there usually is at least some aspect of a skin care regimen they will follow to achieve relief when needed. First I make sure that serious issues (eg, bacterial infections) are addressed. I do mention to patients/caregivers that lack of treatment with topical prescription agents may have biological consequences; for example, there is evidence to support the Atopic March (ie, progression of atopic diseases to food allergies, asthma, etc). Consequences also can include discomfort, reduced quality of life, and negative effects on personal relationships; pediatric patients also may be stigmatized by their peers. Exploration of the root cause of treatment refusal usually yields a helpful discussion with the patient/caregiver about their fears as well as alternative treatment agents. Sometimes I engage the pediatrician/primary care physician, an allergist, or a family member in the discussion to enhance compliance and provide patient/caregiver support. At the very least, most patients/caregivers will adhere to trigger avoidance and barrier repair through application of emollients.

What resources do you recommend to patients for more information?

There are many resources available to patients that may enhance the overall management of eczema. I give my patients an educational handout about eczema as well as a hardcopy of their personal eczema action plan. For pediatric patients, I write the child’s first name and the date to help his or her caregivers remember when they received the plan. Examples of eczema action plans can be found in published resources ranging from simple to complex regimens and should be tailored to the physician’s own patient education and treatment patterns.^4,5 The National Eczema Association Web site (https://nationaleczema.org/) provides many resources for patients, including educational tools and an online community.

Richard Stone, MD

Photo courtesy of ASH

ORLANDO, FL—After almost 10 years, during which time no new drug for acute myeloid leukemia (AML) has been approved, results of the RATIFY trial are available.

In this trial, investigators evaluated midostaurin in combination with chemotherapy for younger patients with FLT3-mutated AML.

Patients who received midostaurin in their regimen instead of placebo experienced significantly longer overall survival (OS) and event-free survival (EFS).

“The primary endpoint of the trial was overall survival—which was very important—uncensored for transplant,” said Richard Stone, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“This is very much a ‘real-world’ trial. We just took patients from the start and saw how they did until the end.”

Dr Stone presented results from the trial during the plenary session of the 2015 ASH Annual Meeting (abstract 6*).

Midostaurin (PKC412), developed as a VEGF and protein kinase C inhibitor, is a known FLT3 inhibitor that specifically inhibits the growth of leukemic cell lines.

As a multi-kinase inhibitor, its potency against FLT3 may be limited, but it is active against both ITD and TKD mutations. Because AML is polyclonal at diagnosis, a multi-targeted inhibitor may have an advantage in newly diagnosed AML.

As a single agent, Dr Stone explained, midostaurin produced few remissions in advanced, mutant AML. But when combined with chemotherapy in a phase 1B study in newly diagnosed patients, it produced encouraging results.

So members of the Alliance for Clinical Trials in Oncology, formerly CALGB, and many other cooperative groups around the world—the AMLSG, CETLAM, ECOG, EORTC, GIMEMA, NCIC, OSHO, PETHEMA, SAL, and SWOG—conducted a phase 3, randomized, double-blind trial of induction and consolidation with or without midostaurin in patients younger than 60 with newly diagnosed FLT3-mutated AML.

The primary endpoint was OS, and secondary endpoints were OS censored and uncensored at the time of transplant, complete remission (CR) rates, EFS, disease-free survival (DFS), and adverse events.

Mark Levis, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, who introduced the plenary presentation, suggested that OS may not be the best primary endpoint for an AML trial, given the long time it takes to complete a trial like this.

He pointed out that, “while we waited for RATIFY to accrue and mature, our approach to the disease changed.” Allogeneic transplant is now often the favored consolidation.

Eligibility criteria

Patients aged 18 to 60 with normal end-organ function and documented AML were eligible to enroll. Patients could not have had acute promyelocytic leukemia.

Their FLT3 mutation had to be centrally determined prior to enrollment by 1 of 9 academic labs around the world, and results had to be obtainable within 48 hours of sample collection.

Patients could receive up to 5 days of hydroxyurea prior to the start of treatment while awaiting the results of the mutation analysis.

Trial design

Investigators randomized patients to induction of daunorubicin and cytarabine with either midostaurin or placebo.

Daunorubicin was administered at 60 mg/m² by intravenous push on days 1-3, cytarabine at 200 mg/m² per day on days 1-7, and midostaurin at 50 mg orally twice a day on days 8-21.

A second cycle of induction was given based on day 21 bone marrow biopsy.

When patients achieved CR, they went on to consolidation with high-dose cytarabine (3 g/m² over 3 hours every 12 hours on days 1, 3, and 5) and either midostaurin at the same induction dose or placebo.

After up to 4 doses of consolidation, patients went on to maintenance therapy for 12 months. This consisted of placebo or midostaurin at the same dose twice daily on days 1-28.

Patient population

The investigators screened 3279 patients younger than 60 years with newly diagnosed AML and found 27% (n=887) to be FLT3-positive.

They randomized 717 patients—81% of the FLT3-positive patients—to either the midostaurin arm (n=360) or the placebo arm (n=357). These 717 patients were evaluable for the intent-to-treat analysis.

The median age was 47.1 (range, 19.0–59.8) in the midostaurin arm and 48.6 (range, 18.0–60.9) in the placebo arm. There were significantly more males in the midostaurin arm (48.1%) than in the placebo arm (40.6%, P=0.045).

And the arms were almost identical for FLT3 stratification. In the midostaurin group, 22.5% had FLT3 TKD (no ITD), 47.5% had an ITD allelic ratio (+/- FLT3 TKD) less than 0.7, and 30.0% had a ratio of 0.7 or more.

In the placebo arm, 22.7% had FLT3 TKD, and 47.6% and 29.7% had ITD allelic ratios less than and greater than 0.7, respectively.

Safety

Rash/desquamation was the only significant difference in grade 3-4 non-hematologic events between the arms, with 13% in the midostaurin arm and 8% in the placebo arm (P=0.02).

Other grade 3-4 non-hematologic events occurring in 10% of patients or more included, in the midostaurin and placebo arms, respectively: febrile neutropenia (81%, 82%), infection (40%, 38%), diarrhea (15%, 16%), hypokalemia (13%, 17%), pain (13%, 13%), other infection (12%, 12%), ALT/SGPT (12%, 9%), and fatigue (9%, 11%).

There were 18 deaths (5%) in the midostaurin arm and 19 (5.3%) in the placebo arm during induction and consolidation treatment.

Efficacy

OS was superior for patients randomized to midostaurin. The median survival was 74.7 months (range, 31.7-not estimable) in the midostaurin arm and 25.6 months (range,18.6-42.9) in the placebo arm (P=0.0076).

Overall, there were 357 deaths, 171 and 186 in the midostaurin and placebo arms, respectively.

The 5-year survival rate was 50.9% for midostaurin and 43.9% for placebo.

EFS was also superior for patients randomized to midostaurin (P=0.0032), at a median of 8.0 months for midostaurin and 3.6 months for placebo. The 5-year EFS was 27.5% for midostaurin and 19.3% for placebo.

The CR rates by day 60 were not significantly different between the arms, at 59% and 53% for midostaurin and placebo, respectively. And the median time to CR was the same in each group, at 35 days.

The survival benefit, both overall and event-free, was consistent regardless of whether the patients were FLT3-ITD high, low, or FLT3-TKD.

The OS and EFS benefits were also consistent in censored and uncensored analyses, despite the high stem cell transplant rate. Four hundred eight patients (57%) received a transplant, 212 in the midostaurin arm and 196 in the placebo arm.

“The trial was positive whether you censored the patients at transplant or you kept following them for the whole time,” Dr Stone said.

He concluded that this type of international collaborative AML study based on genotype at diagnosis is feasible to do. But it took “a lot of collaboration, a lot of cooperation, a lot of persistence, because the trial took a long time to conceive of, conduct, and analyze.”

*Data in the presentation differ from the abstract.

Richard Stone, MD

Photo courtesy of ASH

ORLANDO, FL—After almost 10 years, during which time no new drug for acute myeloid leukemia (AML) has been approved, results of the RATIFY trial are available.

In this trial, investigators evaluated midostaurin in combination with chemotherapy for younger patients with FLT3-mutated AML.

Patients who received midostaurin in their regimen instead of placebo experienced significantly longer overall survival (OS) and event-free survival (EFS).

“The primary endpoint of the trial was overall survival—which was very important—uncensored for transplant,” said Richard Stone, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“This is very much a ‘real-world’ trial. We just took patients from the start and saw how they did until the end.”

Dr Stone presented results from the trial during the plenary session of the 2015 ASH Annual Meeting (abstract 6*).

Midostaurin (PKC412), developed as a VEGF and protein kinase C inhibitor, is a known FLT3 inhibitor that specifically inhibits the growth of leukemic cell lines.

As a multi-kinase inhibitor, its potency against FLT3 may be limited, but it is active against both ITD and TKD mutations. Because AML is polyclonal at diagnosis, a multi-targeted inhibitor may have an advantage in newly diagnosed AML.

As a single agent, Dr Stone explained, midostaurin produced few remissions in advanced, mutant AML. But when combined with chemotherapy in a phase 1B study in newly diagnosed patients, it produced encouraging results.

So members of the Alliance for Clinical Trials in Oncology, formerly CALGB, and many other cooperative groups around the world—the AMLSG, CETLAM, ECOG, EORTC, GIMEMA, NCIC, OSHO, PETHEMA, SAL, and SWOG—conducted a phase 3, randomized, double-blind trial of induction and consolidation with or without midostaurin in patients younger than 60 with newly diagnosed FLT3-mutated AML.

The primary endpoint was OS, and secondary endpoints were OS censored and uncensored at the time of transplant, complete remission (CR) rates, EFS, disease-free survival (DFS), and adverse events.

Mark Levis, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, who introduced the plenary presentation, suggested that OS may not be the best primary endpoint for an AML trial, given the long time it takes to complete a trial like this.

He pointed out that, “while we waited for RATIFY to accrue and mature, our approach to the disease changed.” Allogeneic transplant is now often the favored consolidation.

Eligibility criteria

Patients aged 18 to 60 with normal end-organ function and documented AML were eligible to enroll. Patients could not have had acute promyelocytic leukemia.

Their FLT3 mutation had to be centrally determined prior to enrollment by 1 of 9 academic labs around the world, and results had to be obtainable within 48 hours of sample collection.

Patients could receive up to 5 days of hydroxyurea prior to the start of treatment while awaiting the results of the mutation analysis.

Trial design

Investigators randomized patients to induction of daunorubicin and cytarabine with either midostaurin or placebo.

Daunorubicin was administered at 60 mg/m² by intravenous push on days 1-3, cytarabine at 200 mg/m² per day on days 1-7, and midostaurin at 50 mg orally twice a day on days 8-21.

A second cycle of induction was given based on day 21 bone marrow biopsy.

When patients achieved CR, they went on to consolidation with high-dose cytarabine (3 g/m² over 3 hours every 12 hours on days 1, 3, and 5) and either midostaurin at the same induction dose or placebo.

After up to 4 doses of consolidation, patients went on to maintenance therapy for 12 months. This consisted of placebo or midostaurin at the same dose twice daily on days 1-28.

Patient population

The investigators screened 3279 patients younger than 60 years with newly diagnosed AML and found 27% (n=887) to be FLT3-positive.

They randomized 717 patients—81% of the FLT3-positive patients—to either the midostaurin arm (n=360) or the placebo arm (n=357). These 717 patients were evaluable for the intent-to-treat analysis.

The median age was 47.1 (range, 19.0–59.8) in the midostaurin arm and 48.6 (range, 18.0–60.9) in the placebo arm. There were significantly more males in the midostaurin arm (48.1%) than in the placebo arm (40.6%, P=0.045).

And the arms were almost identical for FLT3 stratification. In the midostaurin group, 22.5% had FLT3 TKD (no ITD), 47.5% had an ITD allelic ratio (+/- FLT3 TKD) less than 0.7, and 30.0% had a ratio of 0.7 or more.

In the placebo arm, 22.7% had FLT3 TKD, and 47.6% and 29.7% had ITD allelic ratios less than and greater than 0.7, respectively.

Safety

Rash/desquamation was the only significant difference in grade 3-4 non-hematologic events between the arms, with 13% in the midostaurin arm and 8% in the placebo arm (P=0.02).

Other grade 3-4 non-hematologic events occurring in 10% of patients or more included, in the midostaurin and placebo arms, respectively: febrile neutropenia (81%, 82%), infection (40%, 38%), diarrhea (15%, 16%), hypokalemia (13%, 17%), pain (13%, 13%), other infection (12%, 12%), ALT/SGPT (12%, 9%), and fatigue (9%, 11%).

There were 18 deaths (5%) in the midostaurin arm and 19 (5.3%) in the placebo arm during induction and consolidation treatment.

Efficacy

OS was superior for patients randomized to midostaurin. The median survival was 74.7 months (range, 31.7-not estimable) in the midostaurin arm and 25.6 months (range,18.6-42.9) in the placebo arm (P=0.0076).

Overall, there were 357 deaths, 171 and 186 in the midostaurin and placebo arms, respectively.

The 5-year survival rate was 50.9% for midostaurin and 43.9% for placebo.

EFS was also superior for patients randomized to midostaurin (P=0.0032), at a median of 8.0 months for midostaurin and 3.6 months for placebo. The 5-year EFS was 27.5% for midostaurin and 19.3% for placebo.

The CR rates by day 60 were not significantly different between the arms, at 59% and 53% for midostaurin and placebo, respectively. And the median time to CR was the same in each group, at 35 days.

The survival benefit, both overall and event-free, was consistent regardless of whether the patients were FLT3-ITD high, low, or FLT3-TKD.

The OS and EFS benefits were also consistent in censored and uncensored analyses, despite the high stem cell transplant rate. Four hundred eight patients (57%) received a transplant, 212 in the midostaurin arm and 196 in the placebo arm.

“The trial was positive whether you censored the patients at transplant or you kept following them for the whole time,” Dr Stone said.

He concluded that this type of international collaborative AML study based on genotype at diagnosis is feasible to do. But it took “a lot of collaboration, a lot of cooperation, a lot of persistence, because the trial took a long time to conceive of, conduct, and analyze.”

*Data in the presentation differ from the abstract.

Richard Stone, MD

Photo courtesy of ASH

ORLANDO, FL—After almost 10 years, during which time no new drug for acute myeloid leukemia (AML) has been approved, results of the RATIFY trial are available.

In this trial, investigators evaluated midostaurin in combination with chemotherapy for younger patients with FLT3-mutated AML.

Patients who received midostaurin in their regimen instead of placebo experienced significantly longer overall survival (OS) and event-free survival (EFS).

“The primary endpoint of the trial was overall survival—which was very important—uncensored for transplant,” said Richard Stone, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“This is very much a ‘real-world’ trial. We just took patients from the start and saw how they did until the end.”

Dr Stone presented results from the trial during the plenary session of the 2015 ASH Annual Meeting (abstract 6*).

Midostaurin (PKC412), developed as a VEGF and protein kinase C inhibitor, is a known FLT3 inhibitor that specifically inhibits the growth of leukemic cell lines.

As a multi-kinase inhibitor, its potency against FLT3 may be limited, but it is active against both ITD and TKD mutations. Because AML is polyclonal at diagnosis, a multi-targeted inhibitor may have an advantage in newly diagnosed AML.

As a single agent, Dr Stone explained, midostaurin produced few remissions in advanced, mutant AML. But when combined with chemotherapy in a phase 1B study in newly diagnosed patients, it produced encouraging results.

So members of the Alliance for Clinical Trials in Oncology, formerly CALGB, and many other cooperative groups around the world—the AMLSG, CETLAM, ECOG, EORTC, GIMEMA, NCIC, OSHO, PETHEMA, SAL, and SWOG—conducted a phase 3, randomized, double-blind trial of induction and consolidation with or without midostaurin in patients younger than 60 with newly diagnosed FLT3-mutated AML.

The primary endpoint was OS, and secondary endpoints were OS censored and uncensored at the time of transplant, complete remission (CR) rates, EFS, disease-free survival (DFS), and adverse events.

Mark Levis, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, who introduced the plenary presentation, suggested that OS may not be the best primary endpoint for an AML trial, given the long time it takes to complete a trial like this.

He pointed out that, “while we waited for RATIFY to accrue and mature, our approach to the disease changed.” Allogeneic transplant is now often the favored consolidation.

Eligibility criteria

Patients aged 18 to 60 with normal end-organ function and documented AML were eligible to enroll. Patients could not have had acute promyelocytic leukemia.

Their FLT3 mutation had to be centrally determined prior to enrollment by 1 of 9 academic labs around the world, and results had to be obtainable within 48 hours of sample collection.

Patients could receive up to 5 days of hydroxyurea prior to the start of treatment while awaiting the results of the mutation analysis.

Trial design

Investigators randomized patients to induction of daunorubicin and cytarabine with either midostaurin or placebo.

Daunorubicin was administered at 60 mg/m² by intravenous push on days 1-3, cytarabine at 200 mg/m² per day on days 1-7, and midostaurin at 50 mg orally twice a day on days 8-21.

A second cycle of induction was given based on day 21 bone marrow biopsy.

When patients achieved CR, they went on to consolidation with high-dose cytarabine (3 g/m² over 3 hours every 12 hours on days 1, 3, and 5) and either midostaurin at the same induction dose or placebo.

After up to 4 doses of consolidation, patients went on to maintenance therapy for 12 months. This consisted of placebo or midostaurin at the same dose twice daily on days 1-28.

Patient population

The investigators screened 3279 patients younger than 60 years with newly diagnosed AML and found 27% (n=887) to be FLT3-positive.

They randomized 717 patients—81% of the FLT3-positive patients—to either the midostaurin arm (n=360) or the placebo arm (n=357). These 717 patients were evaluable for the intent-to-treat analysis.

The median age was 47.1 (range, 19.0–59.8) in the midostaurin arm and 48.6 (range, 18.0–60.9) in the placebo arm. There were significantly more males in the midostaurin arm (48.1%) than in the placebo arm (40.6%, P=0.045).

And the arms were almost identical for FLT3 stratification. In the midostaurin group, 22.5% had FLT3 TKD (no ITD), 47.5% had an ITD allelic ratio (+/- FLT3 TKD) less than 0.7, and 30.0% had a ratio of 0.7 or more.

In the placebo arm, 22.7% had FLT3 TKD, and 47.6% and 29.7% had ITD allelic ratios less than and greater than 0.7, respectively.

Safety

Rash/desquamation was the only significant difference in grade 3-4 non-hematologic events between the arms, with 13% in the midostaurin arm and 8% in the placebo arm (P=0.02).

Other grade 3-4 non-hematologic events occurring in 10% of patients or more included, in the midostaurin and placebo arms, respectively: febrile neutropenia (81%, 82%), infection (40%, 38%), diarrhea (15%, 16%), hypokalemia (13%, 17%), pain (13%, 13%), other infection (12%, 12%), ALT/SGPT (12%, 9%), and fatigue (9%, 11%).

There were 18 deaths (5%) in the midostaurin arm and 19 (5.3%) in the placebo arm during induction and consolidation treatment.

Efficacy

OS was superior for patients randomized to midostaurin. The median survival was 74.7 months (range, 31.7-not estimable) in the midostaurin arm and 25.6 months (range,18.6-42.9) in the placebo arm (P=0.0076).

Overall, there were 357 deaths, 171 and 186 in the midostaurin and placebo arms, respectively.

The 5-year survival rate was 50.9% for midostaurin and 43.9% for placebo.

EFS was also superior for patients randomized to midostaurin (P=0.0032), at a median of 8.0 months for midostaurin and 3.6 months for placebo. The 5-year EFS was 27.5% for midostaurin and 19.3% for placebo.

The CR rates by day 60 were not significantly different between the arms, at 59% and 53% for midostaurin and placebo, respectively. And the median time to CR was the same in each group, at 35 days.

The survival benefit, both overall and event-free, was consistent regardless of whether the patients were FLT3-ITD high, low, or FLT3-TKD.

The OS and EFS benefits were also consistent in censored and uncensored analyses, despite the high stem cell transplant rate. Four hundred eight patients (57%) received a transplant, 212 in the midostaurin arm and 196 in the placebo arm.

“The trial was positive whether you censored the patients at transplant or you kept following them for the whole time,” Dr Stone said.

He concluded that this type of international collaborative AML study based on genotype at diagnosis is feasible to do. But it took “a lot of collaboration, a lot of cooperation, a lot of persistence, because the trial took a long time to conceive of, conduct, and analyze.”

*Data in the presentation differ from the abstract.

Rivaroxaban

ORLANDO, FL—“Real-world” data appear to confirm phase 3 results with rivaroxaban in patients who have deep vein thrombosis (DVT), with or without concomitant pulmonary embolism (PE).

Results of the phase 4 XALIA study suggest that, in clinical practice, the rates of major bleeding and recurrent venous thromboembolism (VTE) in patients taking rivaroxaban are generally consistent with results of the phase 3 EINSTEIN-DVT study.

Investigators noted, however, that methodological and other differences between the studies limit the ability to directly compare results of XALIA and EINSTEIN-DVT.

Alexander G. G. Turpie, MD, of McMaster University and Hamilton Health Sciences in Hamilton, Ontario, Canada, and his colleagues reported data from the XALIA study at the 2015 ASH Annual Meeting (abstract 894) and in The Lancet Haematology.

The study was sponsored by Janssen and Bayer HealthCare.

“The real-world insights from XALIA confirm the positive benefit-risk profile of rivaroxaban for the treatment of deep vein thrombosis that was observed in the phase 3 EINSTEIN-DVT study, signaling that the medicine is performing as expected in patients that physicians typically see in everyday clinical practice,” Dr Turpie said.

Study design

For the XALIA study, investigators compared once-daily rivaroxaban to standard anticoagulation in patients with DVT, with or without concomitant PE. Standard anticoagulation was considered initial treatment with heparin, low-molecular-weight heparin, or fondaparinux, typically overlapping with and followed by warfarin.

The study enrolled 5142 patients age 18 and older. Patients were enrolled between June 2012 and March 2014 and followed for at least 12 months.

A total of 4768 patients were included in the primary analysis—2619 in the rivaroxaban group and 2149 in the standard anticoagulation group.

But the investigators also completed a propensity-score analysis to address differences in baseline characteristics and help correct for any selection bias. There were 4515 patients in this analysis—2505 in the rivaroxaban group and 2010 in the standard anticoagulation group.

The primary outcomes were major bleeding, recurrent VTE, and all-cause mortality.

Results

In the propensity score-adjusted population, major bleeding occurred in 0.8% of patients receiving rivaroxaban and 2.1% of those receiving standard anticoagulation (hazard ratio[HR]=0.77, P=0.44).

There were no fatal bleeding events in the rivaroxaban group and 2 fatal bleeding events in the standard anticoagulation group.

In EINSTEIN-DVT, major bleeding occurred in 0.8% of patients taking rivaroxaban, and there was 1 fatal bleeding event.

In XALIA (propensity score-adjusted population), VTE recurred in 1.4% of patients receiving rivaroxaban and 2.3% of those receiving standard anticoagulation (HR=0.91, P=0.72).

In EINSTEIN-DVT, VTE recurred in 2.1% of patients taking rivaroxaban.

In XALIA (propensity score-adjusted population), the rate of all-cause mortality was 0.4% in patients taking rivaroxaban and 3.4% in those receiving standard anticoagulation (HR=0.51, P=0.07).

In EINSTEIN-DVT, the rate of all-cause mortality was 2.2% in patients taking rivaroxaban.

Rivaroxaban

ORLANDO, FL—“Real-world” data appear to confirm phase 3 results with rivaroxaban in patients who have deep vein thrombosis (DVT), with or without concomitant pulmonary embolism (PE).

Results of the phase 4 XALIA study suggest that, in clinical practice, the rates of major bleeding and recurrent venous thromboembolism (VTE) in patients taking rivaroxaban are generally consistent with results of the phase 3 EINSTEIN-DVT study.

Investigators noted, however, that methodological and other differences between the studies limit the ability to directly compare results of XALIA and EINSTEIN-DVT.

Alexander G. G. Turpie, MD, of McMaster University and Hamilton Health Sciences in Hamilton, Ontario, Canada, and his colleagues reported data from the XALIA study at the 2015 ASH Annual Meeting (abstract 894) and in The Lancet Haematology.

The study was sponsored by Janssen and Bayer HealthCare.

“The real-world insights from XALIA confirm the positive benefit-risk profile of rivaroxaban for the treatment of deep vein thrombosis that was observed in the phase 3 EINSTEIN-DVT study, signaling that the medicine is performing as expected in patients that physicians typically see in everyday clinical practice,” Dr Turpie said.

Study design

For the XALIA study, investigators compared once-daily rivaroxaban to standard anticoagulation in patients with DVT, with or without concomitant PE. Standard anticoagulation was considered initial treatment with heparin, low-molecular-weight heparin, or fondaparinux, typically overlapping with and followed by warfarin.

The study enrolled 5142 patients age 18 and older. Patients were enrolled between June 2012 and March 2014 and followed for at least 12 months.

A total of 4768 patients were included in the primary analysis—2619 in the rivaroxaban group and 2149 in the standard anticoagulation group.

But the investigators also completed a propensity-score analysis to address differences in baseline characteristics and help correct for any selection bias. There were 4515 patients in this analysis—2505 in the rivaroxaban group and 2010 in the standard anticoagulation group.

The primary outcomes were major bleeding, recurrent VTE, and all-cause mortality.

Results

In the propensity score-adjusted population, major bleeding occurred in 0.8% of patients receiving rivaroxaban and 2.1% of those receiving standard anticoagulation (hazard ratio[HR]=0.77, P=0.44).

There were no fatal bleeding events in the rivaroxaban group and 2 fatal bleeding events in the standard anticoagulation group.

In EINSTEIN-DVT, major bleeding occurred in 0.8% of patients taking rivaroxaban, and there was 1 fatal bleeding event.

In XALIA (propensity score-adjusted population), VTE recurred in 1.4% of patients receiving rivaroxaban and 2.3% of those receiving standard anticoagulation (HR=0.91, P=0.72).

In EINSTEIN-DVT, VTE recurred in 2.1% of patients taking rivaroxaban.

In XALIA (propensity score-adjusted population), the rate of all-cause mortality was 0.4% in patients taking rivaroxaban and 3.4% in those receiving standard anticoagulation (HR=0.51, P=0.07).

In EINSTEIN-DVT, the rate of all-cause mortality was 2.2% in patients taking rivaroxaban.

Rivaroxaban

ORLANDO, FL—“Real-world” data appear to confirm phase 3 results with rivaroxaban in patients who have deep vein thrombosis (DVT), with or without concomitant pulmonary embolism (PE).

Results of the phase 4 XALIA study suggest that, in clinical practice, the rates of major bleeding and recurrent venous thromboembolism (VTE) in patients taking rivaroxaban are generally consistent with results of the phase 3 EINSTEIN-DVT study.

Investigators noted, however, that methodological and other differences between the studies limit the ability to directly compare results of XALIA and EINSTEIN-DVT.

Alexander G. G. Turpie, MD, of McMaster University and Hamilton Health Sciences in Hamilton, Ontario, Canada, and his colleagues reported data from the XALIA study at the 2015 ASH Annual Meeting (abstract 894) and in The Lancet Haematology.

The study was sponsored by Janssen and Bayer HealthCare.

“The real-world insights from XALIA confirm the positive benefit-risk profile of rivaroxaban for the treatment of deep vein thrombosis that was observed in the phase 3 EINSTEIN-DVT study, signaling that the medicine is performing as expected in patients that physicians typically see in everyday clinical practice,” Dr Turpie said.

Study design

For the XALIA study, investigators compared once-daily rivaroxaban to standard anticoagulation in patients with DVT, with or without concomitant PE. Standard anticoagulation was considered initial treatment with heparin, low-molecular-weight heparin, or fondaparinux, typically overlapping with and followed by warfarin.

The study enrolled 5142 patients age 18 and older. Patients were enrolled between June 2012 and March 2014 and followed for at least 12 months.

A total of 4768 patients were included in the primary analysis—2619 in the rivaroxaban group and 2149 in the standard anticoagulation group.

But the investigators also completed a propensity-score analysis to address differences in baseline characteristics and help correct for any selection bias. There were 4515 patients in this analysis—2505 in the rivaroxaban group and 2010 in the standard anticoagulation group.

The primary outcomes were major bleeding, recurrent VTE, and all-cause mortality.

Results

In the propensity score-adjusted population, major bleeding occurred in 0.8% of patients receiving rivaroxaban and 2.1% of those receiving standard anticoagulation (hazard ratio[HR]=0.77, P=0.44).

There were no fatal bleeding events in the rivaroxaban group and 2 fatal bleeding events in the standard anticoagulation group.

In EINSTEIN-DVT, major bleeding occurred in 0.8% of patients taking rivaroxaban, and there was 1 fatal bleeding event.

In XALIA (propensity score-adjusted population), VTE recurred in 1.4% of patients receiving rivaroxaban and 2.3% of those receiving standard anticoagulation (HR=0.91, P=0.72).

In EINSTEIN-DVT, VTE recurred in 2.1% of patients taking rivaroxaban.

In XALIA (propensity score-adjusted population), the rate of all-cause mortality was 0.4% in patients taking rivaroxaban and 3.4% in those receiving standard anticoagulation (HR=0.51, P=0.07).

In EINSTEIN-DVT, the rate of all-cause mortality was 2.2% in patients taking rivaroxaban.

 

 

2015 ASH Annual Meeting

Photo courtesy of ASH

 

ORLANDO, FL—A 3-drug regimen is likely not worth pursuing as a first-line treatment option for follicular lymphoma (FL), according to a presentation at the 2015 ASH Annual Meeting.

In a phase 1 study, combination ibrutinib, rituximab, and lenalidomide did not provide any response benefit over that previously observed with rituximab and lenalidomide.

But the triplet increased toxicity—particularly the incidence of rash—and necessitated dose modifications.

Chaitra S. Ujjani, MD, of Georgetown University Hospital in Washington, DC, presented these results at the meeting as abstract 471.*

“The combination of rituximab and lenalidomide has demonstrated remarkable activity in follicular lymphoma,” Dr Ujjani began.

She noted that, in the CALGB 50401 trial of relapsed FL (Leonard et al. JCO 2015), the combination elicited an overall response rate (ORR) of 76% and a complete response (CR) rate of 39%, and the 2-year time to progression was 52%.

In the CALGB 50803 trial of previously untreated FL (Martin et al. ASCO 2014, 8521), the regimen produced an ORR of 96%, a CR rate of 71%, and a 2-year progression-free survival (PFS) of 89%. In another trial of previously untreated FL (Fowler et al. Lanc Onc 2014), the ORR was 90%, the CR rate was 80%, and the 3-year PFS was 79%.

Ibrutinib has also demonstrated activity in FL, Dr Ujjani pointed out. In a phase 1 study of relapsed FL (Fowler et al. ASH 2012), the drug produced an ORR of 55%, 3 of 11 patients achieved a CR, and the median PFS was 13.4 months.

In a phase 2 study of ibrutinib in relapsed FL (Bartlett et al. ASH 2014, 800), the ORR was 30%, 1 of 40 patients achieved a CR, and the median PFS was 9.9 months.

With this in mind, Dr Ujjani and her colleagues conducted the A051103 trial to determine the activity and tolerability of rituximab, lenalidomide, and ibrutinib in previously untreated patients with FL.

Study design

The study enrolled patients with grade 1-3a FL; stage III, IV, or bulky stage II disease; an ECOG performance status less than 2; and adequate organ function.

They received 4 doses of rituximab at 375 mg/m² on days 1, 8, 15, and 22 of cycle 1 (28 days). They received 4 additional doses (375 mg/m²) on day 1 of cycles 4, 6, 8, and 10.

The patients received lenalidomide according to their assigned dosing cohort on days 1 to 21 for 18 cycles. They received daily ibrutinib according to their assigned dosing cohort until progression or unacceptable toxicity.

The study had a 3+3 dose-escalation design. Dose level (DL) 0 was lenalidomide at 15 mg and ibrutinib at 420 mg, DL1 was lenalidomide at 15 mg and ibrutinib at 560 mg, and DL2 was lenalidomide at 20 mg and ibrutinib at 560 mg.

Patients also received allopurinol at 300 mg daily for tumor lysis prophylaxis and aspirin as thromboprophylaxis while on lenalidomide.

The researchers assessed dose-limiting toxicities (DLTs) weekly during cycle 1. Given the known incidence of rash with lenalidomide, grade 3 rash that resolved to less than grade 2 within 10 days was not included as a DLT.

Once the maximum-tolerated dose was determined, there was a 10-patient expansion cohort.

Patients and treatment

Twenty-two patients were enrolled between June 2013 and May 2015. Their median age was 53.5 years (range, 36-81), and 68% were male.

Seventy-three percent of patients had grade 1/2 disease, and 77% had stage IV disease. By FLIPI, 18% of patients were low-risk, 55% were intermediate-risk, and 27% were high-risk.

Three patients were treated at DL0, 3 at DL1, and 16 at DL2. There were no DLTs reported at any dose level.

However, 11 patients required dose reductions due to toxicity (7 due to rash), and 12 patients ultimately discontinued treatment.

Reasons for discontinuation included progression (n=2), new diagnosis of carcinoma requiring systemic therapy (n=2), patient decision (n=3), and adverse events (n=6), including grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1), hypertension (n=1), and depression (n=1). (One patient discontinued due to rash and progression.)

Adverse events

Dr Ujjani said the hematologic toxicity profile was similar to that observed with rituximab and lenalidomide in the front-line setting. Grade 3/4 hematologic toxicities included neutropenia (18.2%), thrombocytopenia (4.5%), anemia (4.5%), and lymphopenia (4.5%).

The most common non-hematologic toxicities (occurring in more than 20% of patients) were rash, diarrhea, fatigue, infusion-related reactions, nausea, infection, and neoplasms. There were no grade 4 non-hematologic toxicities.

Compared to rituximab and lenalidomide, the triplet was associated with an increase in rash, diarrhea, arthralgia, and neoplasm. There were 2 cutaneous neoplasms and 3 carcinomas.

Rash

“While no protocol-defined DLTs were observed, the regimen was associated with clinically significant rash,” Dr Ujjani noted. “Rash may have been related to individual study drugs or drug-drug interactions.”

Rash occurred in 82% of patients overall, 100% of patients treated at DL0, 67% at DL1, and 81% at DL2. The incidence of grade 1/2 rash was 46% overall, 67% at DL0, 33% at DL1, and 44% at DL2. The incidence of grade 3 rash was 36% overall, 33% at DL0 and DL1, and 38% at DL2.

The incidence of rash was similar whether or not patients received allopurinol. Ten of 11 patients on allopurinol had a rash, and 8 of 11 patients not on allopurinol had a rash.

“The time of [rash] onset was typically during cycle 1 but was seen as late as cycle 5,” Dr Ujjani said. “Grade 1 and 2 rashes resolved spontaneously without dose modification. The incidence of these milder rashes were comparable to our prior reports of rituximab and lenalidomide.”

“Grade 3 rash, however, occurred in 36% of patients, which is significantly higher than [with] rituximab and lenalidomide, [which is] typically 7% to 8%, or single-agent ibrutinib, which is about 3% to 4%.”

Patients with grade 3 rash were managed with supportive care, including acetaminophen, diphenhydramine, and oral corticosteroids.

All but 1 patient (7/8) had dose delays and reductions due to rash. One patient withdrew from the study because of rash, and 1 patient withdrew because of disease progression that occurred during a dose delay for rash.

Response and survival

The ORR was 95% for the entire cohort, 100% at DL0 and DL1 and 94% at DL2. The CR/unconfirmed CR rate was 63% overall, 67% at DL0, 33% at DL1, and 69% at DL2.

The partial response rate was 32% overall, 33% at DL0, 67% at DL1, and 25% at DL2. Five percent of patients had stable disease, all at DL2 (6% of this group).

The median time to first response was 2.3 months (range, 1.9 to 11.1). And the median time to best response was 5.5 months (range, 1.9 to 20.2).

At a median follow-up of 12.3 months, all patients are still alive. The 12-month PFS is 84%.

“Preliminary response data were similar to the prior CALGB/Alliance study of rituximab and lenalidomide,” Dr Ujjani noted. “However, given the increased toxicity and required dose modifications, the additional benefit of a third agent is not apparent, and further investigation of the triplet in this setting seems unwarranted.”

*Data in the abstract differ from data presented at the meeting.

 

 

2015 ASH Annual Meeting

Photo courtesy of ASH

 

ORLANDO, FL—A 3-drug regimen is likely not worth pursuing as a first-line treatment option for follicular lymphoma (FL), according to a presentation at the 2015 ASH Annual Meeting.

In a phase 1 study, combination ibrutinib, rituximab, and lenalidomide did not provide any response benefit over that previously observed with rituximab and lenalidomide.

But the triplet increased toxicity—particularly the incidence of rash—and necessitated dose modifications.

Chaitra S. Ujjani, MD, of Georgetown University Hospital in Washington, DC, presented these results at the meeting as abstract 471.*

“The combination of rituximab and lenalidomide has demonstrated remarkable activity in follicular lymphoma,” Dr Ujjani began.

She noted that, in the CALGB 50401 trial of relapsed FL (Leonard et al. JCO 2015), the combination elicited an overall response rate (ORR) of 76% and a complete response (CR) rate of 39%, and the 2-year time to progression was 52%.

In the CALGB 50803 trial of previously untreated FL (Martin et al. ASCO 2014, 8521), the regimen produced an ORR of 96%, a CR rate of 71%, and a 2-year progression-free survival (PFS) of 89%. In another trial of previously untreated FL (Fowler et al. Lanc Onc 2014), the ORR was 90%, the CR rate was 80%, and the 3-year PFS was 79%.

Ibrutinib has also demonstrated activity in FL, Dr Ujjani pointed out. In a phase 1 study of relapsed FL (Fowler et al. ASH 2012), the drug produced an ORR of 55%, 3 of 11 patients achieved a CR, and the median PFS was 13.4 months.

In a phase 2 study of ibrutinib in relapsed FL (Bartlett et al. ASH 2014, 800), the ORR was 30%, 1 of 40 patients achieved a CR, and the median PFS was 9.9 months.

With this in mind, Dr Ujjani and her colleagues conducted the A051103 trial to determine the activity and tolerability of rituximab, lenalidomide, and ibrutinib in previously untreated patients with FL.

Study design

The study enrolled patients with grade 1-3a FL; stage III, IV, or bulky stage II disease; an ECOG performance status less than 2; and adequate organ function.

They received 4 doses of rituximab at 375 mg/m² on days 1, 8, 15, and 22 of cycle 1 (28 days). They received 4 additional doses (375 mg/m²) on day 1 of cycles 4, 6, 8, and 10.

The patients received lenalidomide according to their assigned dosing cohort on days 1 to 21 for 18 cycles. They received daily ibrutinib according to their assigned dosing cohort until progression or unacceptable toxicity.

The study had a 3+3 dose-escalation design. Dose level (DL) 0 was lenalidomide at 15 mg and ibrutinib at 420 mg, DL1 was lenalidomide at 15 mg and ibrutinib at 560 mg, and DL2 was lenalidomide at 20 mg and ibrutinib at 560 mg.

Patients also received allopurinol at 300 mg daily for tumor lysis prophylaxis and aspirin as thromboprophylaxis while on lenalidomide.

The researchers assessed dose-limiting toxicities (DLTs) weekly during cycle 1. Given the known incidence of rash with lenalidomide, grade 3 rash that resolved to less than grade 2 within 10 days was not included as a DLT.

Once the maximum-tolerated dose was determined, there was a 10-patient expansion cohort.

Patients and treatment

Twenty-two patients were enrolled between June 2013 and May 2015. Their median age was 53.5 years (range, 36-81), and 68% were male.

Seventy-three percent of patients had grade 1/2 disease, and 77% had stage IV disease. By FLIPI, 18% of patients were low-risk, 55% were intermediate-risk, and 27% were high-risk.

Three patients were treated at DL0, 3 at DL1, and 16 at DL2. There were no DLTs reported at any dose level.

However, 11 patients required dose reductions due to toxicity (7 due to rash), and 12 patients ultimately discontinued treatment.

Reasons for discontinuation included progression (n=2), new diagnosis of carcinoma requiring systemic therapy (n=2), patient decision (n=3), and adverse events (n=6), including grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1), hypertension (n=1), and depression (n=1). (One patient discontinued due to rash and progression.)

Adverse events

Dr Ujjani said the hematologic toxicity profile was similar to that observed with rituximab and lenalidomide in the front-line setting. Grade 3/4 hematologic toxicities included neutropenia (18.2%), thrombocytopenia (4.5%), anemia (4.5%), and lymphopenia (4.5%).

The most common non-hematologic toxicities (occurring in more than 20% of patients) were rash, diarrhea, fatigue, infusion-related reactions, nausea, infection, and neoplasms. There were no grade 4 non-hematologic toxicities.

Compared to rituximab and lenalidomide, the triplet was associated with an increase in rash, diarrhea, arthralgia, and neoplasm. There were 2 cutaneous neoplasms and 3 carcinomas.

Rash

“While no protocol-defined DLTs were observed, the regimen was associated with clinically significant rash,” Dr Ujjani noted. “Rash may have been related to individual study drugs or drug-drug interactions.”

Rash occurred in 82% of patients overall, 100% of patients treated at DL0, 67% at DL1, and 81% at DL2. The incidence of grade 1/2 rash was 46% overall, 67% at DL0, 33% at DL1, and 44% at DL2. The incidence of grade 3 rash was 36% overall, 33% at DL0 and DL1, and 38% at DL2.

The incidence of rash was similar whether or not patients received allopurinol. Ten of 11 patients on allopurinol had a rash, and 8 of 11 patients not on allopurinol had a rash.

“The time of [rash] onset was typically during cycle 1 but was seen as late as cycle 5,” Dr Ujjani said. “Grade 1 and 2 rashes resolved spontaneously without dose modification. The incidence of these milder rashes were comparable to our prior reports of rituximab and lenalidomide.”

“Grade 3 rash, however, occurred in 36% of patients, which is significantly higher than [with] rituximab and lenalidomide, [which is] typically 7% to 8%, or single-agent ibrutinib, which is about 3% to 4%.”

Patients with grade 3 rash were managed with supportive care, including acetaminophen, diphenhydramine, and oral corticosteroids.

All but 1 patient (7/8) had dose delays and reductions due to rash. One patient withdrew from the study because of rash, and 1 patient withdrew because of disease progression that occurred during a dose delay for rash.

Response and survival

The ORR was 95% for the entire cohort, 100% at DL0 and DL1 and 94% at DL2. The CR/unconfirmed CR rate was 63% overall, 67% at DL0, 33% at DL1, and 69% at DL2.

The partial response rate was 32% overall, 33% at DL0, 67% at DL1, and 25% at DL2. Five percent of patients had stable disease, all at DL2 (6% of this group).

The median time to first response was 2.3 months (range, 1.9 to 11.1). And the median time to best response was 5.5 months (range, 1.9 to 20.2).

At a median follow-up of 12.3 months, all patients are still alive. The 12-month PFS is 84%.

“Preliminary response data were similar to the prior CALGB/Alliance study of rituximab and lenalidomide,” Dr Ujjani noted. “However, given the increased toxicity and required dose modifications, the additional benefit of a third agent is not apparent, and further investigation of the triplet in this setting seems unwarranted.”

*Data in the abstract differ from data presented at the meeting.

 

 

2015 ASH Annual Meeting

Photo courtesy of ASH

 

ORLANDO, FL—A 3-drug regimen is likely not worth pursuing as a first-line treatment option for follicular lymphoma (FL), according to a presentation at the 2015 ASH Annual Meeting.

In a phase 1 study, combination ibrutinib, rituximab, and lenalidomide did not provide any response benefit over that previously observed with rituximab and lenalidomide.

But the triplet increased toxicity—particularly the incidence of rash—and necessitated dose modifications.

Chaitra S. Ujjani, MD, of Georgetown University Hospital in Washington, DC, presented these results at the meeting as abstract 471.*

“The combination of rituximab and lenalidomide has demonstrated remarkable activity in follicular lymphoma,” Dr Ujjani began.

She noted that, in the CALGB 50401 trial of relapsed FL (Leonard et al. JCO 2015), the combination elicited an overall response rate (ORR) of 76% and a complete response (CR) rate of 39%, and the 2-year time to progression was 52%.

In the CALGB 50803 trial of previously untreated FL (Martin et al. ASCO 2014, 8521), the regimen produced an ORR of 96%, a CR rate of 71%, and a 2-year progression-free survival (PFS) of 89%. In another trial of previously untreated FL (Fowler et al. Lanc Onc 2014), the ORR was 90%, the CR rate was 80%, and the 3-year PFS was 79%.

Ibrutinib has also demonstrated activity in FL, Dr Ujjani pointed out. In a phase 1 study of relapsed FL (Fowler et al. ASH 2012), the drug produced an ORR of 55%, 3 of 11 patients achieved a CR, and the median PFS was 13.4 months.

In a phase 2 study of ibrutinib in relapsed FL (Bartlett et al. ASH 2014, 800), the ORR was 30%, 1 of 40 patients achieved a CR, and the median PFS was 9.9 months.

With this in mind, Dr Ujjani and her colleagues conducted the A051103 trial to determine the activity and tolerability of rituximab, lenalidomide, and ibrutinib in previously untreated patients with FL.

Study design

The study enrolled patients with grade 1-3a FL; stage III, IV, or bulky stage II disease; an ECOG performance status less than 2; and adequate organ function.

They received 4 doses of rituximab at 375 mg/m² on days 1, 8, 15, and 22 of cycle 1 (28 days). They received 4 additional doses (375 mg/m²) on day 1 of cycles 4, 6, 8, and 10.

The patients received lenalidomide according to their assigned dosing cohort on days 1 to 21 for 18 cycles. They received daily ibrutinib according to their assigned dosing cohort until progression or unacceptable toxicity.

The study had a 3+3 dose-escalation design. Dose level (DL) 0 was lenalidomide at 15 mg and ibrutinib at 420 mg, DL1 was lenalidomide at 15 mg and ibrutinib at 560 mg, and DL2 was lenalidomide at 20 mg and ibrutinib at 560 mg.

Patients also received allopurinol at 300 mg daily for tumor lysis prophylaxis and aspirin as thromboprophylaxis while on lenalidomide.

The researchers assessed dose-limiting toxicities (DLTs) weekly during cycle 1. Given the known incidence of rash with lenalidomide, grade 3 rash that resolved to less than grade 2 within 10 days was not included as a DLT.

Once the maximum-tolerated dose was determined, there was a 10-patient expansion cohort.

Patients and treatment

Twenty-two patients were enrolled between June 2013 and May 2015. Their median age was 53.5 years (range, 36-81), and 68% were male.

Seventy-three percent of patients had grade 1/2 disease, and 77% had stage IV disease. By FLIPI, 18% of patients were low-risk, 55% were intermediate-risk, and 27% were high-risk.

Three patients were treated at DL0, 3 at DL1, and 16 at DL2. There were no DLTs reported at any dose level.

However, 11 patients required dose reductions due to toxicity (7 due to rash), and 12 patients ultimately discontinued treatment.

Reasons for discontinuation included progression (n=2), new diagnosis of carcinoma requiring systemic therapy (n=2), patient decision (n=3), and adverse events (n=6), including grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1), hypertension (n=1), and depression (n=1). (One patient discontinued due to rash and progression.)

Adverse events

Dr Ujjani said the hematologic toxicity profile was similar to that observed with rituximab and lenalidomide in the front-line setting. Grade 3/4 hematologic toxicities included neutropenia (18.2%), thrombocytopenia (4.5%), anemia (4.5%), and lymphopenia (4.5%).

The most common non-hematologic toxicities (occurring in more than 20% of patients) were rash, diarrhea, fatigue, infusion-related reactions, nausea, infection, and neoplasms. There were no grade 4 non-hematologic toxicities.

Compared to rituximab and lenalidomide, the triplet was associated with an increase in rash, diarrhea, arthralgia, and neoplasm. There were 2 cutaneous neoplasms and 3 carcinomas.

Rash

“While no protocol-defined DLTs were observed, the regimen was associated with clinically significant rash,” Dr Ujjani noted. “Rash may have been related to individual study drugs or drug-drug interactions.”

Rash occurred in 82% of patients overall, 100% of patients treated at DL0, 67% at DL1, and 81% at DL2. The incidence of grade 1/2 rash was 46% overall, 67% at DL0, 33% at DL1, and 44% at DL2. The incidence of grade 3 rash was 36% overall, 33% at DL0 and DL1, and 38% at DL2.

The incidence of rash was similar whether or not patients received allopurinol. Ten of 11 patients on allopurinol had a rash, and 8 of 11 patients not on allopurinol had a rash.

“The time of [rash] onset was typically during cycle 1 but was seen as late as cycle 5,” Dr Ujjani said. “Grade 1 and 2 rashes resolved spontaneously without dose modification. The incidence of these milder rashes were comparable to our prior reports of rituximab and lenalidomide.”

“Grade 3 rash, however, occurred in 36% of patients, which is significantly higher than [with] rituximab and lenalidomide, [which is] typically 7% to 8%, or single-agent ibrutinib, which is about 3% to 4%.”

Patients with grade 3 rash were managed with supportive care, including acetaminophen, diphenhydramine, and oral corticosteroids.

All but 1 patient (7/8) had dose delays and reductions due to rash. One patient withdrew from the study because of rash, and 1 patient withdrew because of disease progression that occurred during a dose delay for rash.

Response and survival

The ORR was 95% for the entire cohort, 100% at DL0 and DL1 and 94% at DL2. The CR/unconfirmed CR rate was 63% overall, 67% at DL0, 33% at DL1, and 69% at DL2.

The partial response rate was 32% overall, 33% at DL0, 67% at DL1, and 25% at DL2. Five percent of patients had stable disease, all at DL2 (6% of this group).

The median time to first response was 2.3 months (range, 1.9 to 11.1). And the median time to best response was 5.5 months (range, 1.9 to 20.2).

At a median follow-up of 12.3 months, all patients are still alive. The 12-month PFS is 84%.

“Preliminary response data were similar to the prior CALGB/Alliance study of rituximab and lenalidomide,” Dr Ujjani noted. “However, given the increased toxicity and required dose modifications, the additional benefit of a third agent is not apparent, and further investigation of the triplet in this setting seems unwarranted.”

*Data in the abstract differ from data presented at the meeting.

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the use of Bendeka, a liquid, low-volume (50 mL), 10-minute infusion formulation of bendamustine hydrochloride.

Bendeka is now approved to treat patients with chronic lymphocytic leukemia (CLL) and patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

The FDA previously granted Bendeka orphan drug designation for CLL and indolent B-cell NHL.

Under a license agreement with Eagle Pharmaceuticals, Inc., Teva Pharmaceutical Industries Ltd. is responsible for all US commercial activities for Bendeka.

Teva said it expects to make Bendeka commercially available to prescribers during the first quarter of 2016. For details on the drug, see the full prescribing information.

Teva also markets bendamustine hydrochloride under the trade name Treanda, which is FDA-approved to treat CLL and NHL and is available in 2 formulations:

• A solution of 45 mg/0.5 mL or 180 mg/2 mL in a single-dose vial
• A 25 mg or 100 mg lyophilized powder in a single-dose vial for reconstitution.
  

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the use of Bendeka, a liquid, low-volume (50 mL), 10-minute infusion formulation of bendamustine hydrochloride.

Bendeka is now approved to treat patients with chronic lymphocytic leukemia (CLL) and patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

The FDA previously granted Bendeka orphan drug designation for CLL and indolent B-cell NHL.

Under a license agreement with Eagle Pharmaceuticals, Inc., Teva Pharmaceutical Industries Ltd. is responsible for all US commercial activities for Bendeka.

Teva said it expects to make Bendeka commercially available to prescribers during the first quarter of 2016. For details on the drug, see the full prescribing information.

Teva also markets bendamustine hydrochloride under the trade name Treanda, which is FDA-approved to treat CLL and NHL and is available in 2 formulations:

• A solution of 45 mg/0.5 mL or 180 mg/2 mL in a single-dose vial
• A 25 mg or 100 mg lyophilized powder in a single-dose vial for reconstitution.
  

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the use of Bendeka, a liquid, low-volume (50 mL), 10-minute infusion formulation of bendamustine hydrochloride.

Bendeka is now approved to treat patients with chronic lymphocytic leukemia (CLL) and patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

The FDA previously granted Bendeka orphan drug designation for CLL and indolent B-cell NHL.

Under a license agreement with Eagle Pharmaceuticals, Inc., Teva Pharmaceutical Industries Ltd. is responsible for all US commercial activities for Bendeka.

Teva said it expects to make Bendeka commercially available to prescribers during the first quarter of 2016. For details on the drug, see the full prescribing information.

Teva also markets bendamustine hydrochloride under the trade name Treanda, which is FDA-approved to treat CLL and NHL and is available in 2 formulations:

• A solution of 45 mg/0.5 mL or 180 mg/2 mL in a single-dose vial
• A 25 mg or 100 mg lyophilized powder in a single-dose vial for reconstitution.
  

In the United States, we treat almost all infections for 10 days. Why? In France, most infections are treated for 8 days. In the U.K., most infections are treated for 5 days. In many other countries, infections are treated until symptomatic improvement occurs. Can everyone outside the United States be wrong? What is the evidence base for the various recommended durations? Moreover, what is the harm in treating for longer than necessary?

The U.S. tradition of 10 days’ treatment for infections arose from the 1940 trials of injectable penicillin for prevention of acute rheumatic fever in military recruits who had group A streptococcal pharyngitis. Injections of penicillin G mixed in peanut oil produced therapeutic levels of penicillin for about 3 days. Soldiers who received three sequential injections had the lowest occurrence of rheumatic fever; two injections were not as good and four injections did not add to the prevention rate. So three injections meant 9 days’ treatment; 9 days was rounded up to 10 days, and there you have it.

We have come a long way since the 1940s. For strep throat, we now have three approved antibiotics for 5 days’ treatment: cefdinir, cefpodoxime proxetil, and azithromycin, all evidence based and U.S. Food and Drug Administration approved. One large study was done in the 1980s with cefadroxil for 5 days, and that duration was as effective in strep eradication as was 10 days, but the company never pursued the 5-day indication.

The optimal duration of antibiotic treatment is generally considered to be 10 days in the United States, however, there is scant evidence base for that recommendation. The recent American Academy of Pediatrics/American Academy of Family Physicians guidelines endorse 10 days of treatment duration as the standard for most acute otitis media (AOM) (Pediatrics 2013;131[3]:e964-99), but acknowledge that shorter treatment regimens may be as effective. Specifically, the guideline states: “A 7-day course of oral antibiotic appears to be equally effective in children 2- to 5 years of age with mild to moderate AOM. For children 6 years and older with mild to moderate AOM symptoms, a 5- to 7-day course is adequate treatment.” A systematic analysis and a meta-analysis have concluded that 5 days’ duration of antibiotics is as effective as 10 days’ treatment for all children over age 2 years and only marginally inferior to 10 days for children under the age of 2 years old (Cochrane Database Syst Rev. 2010;[9]:CD001095).

Thirty years ago, our group and others began to do studies involving “double tympanocentesis,” where an ear tap was done at time of diagnosis and again 3-5 days later to prove bacterial cure for various antibiotics that were in trials. We learned that if the organism was sensitive to the antibiotic chosen, then it was dead by days 3-5. Most of the failures were due to resistant bacteria. So treating longer was not going to help. It was time to change the antibiotic if clinical improvement had not occurred. Our group published a study 15 years ago of 2,172 children comparing 5-, 7-, and 10-days’ treatment of AOM, and concluded that 5 days’ treatment was equivalent to 7- and 10-days of treatment for all ages unless the child had a perforated tympanic membrane or the child had been treated for AOM within the preceding month since recently treated AOM was associated with more frequent causation of AOM by resistant bacteria and with a continued inflamed middle ear mucosa (Otolaryngol Head Neck Surg. 2001 Apr;124[4]:381-7). Since then we have treated all children with ear infections for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins unless the eardrum had perforated or the child had a recurrent AOM within the prior 30 days. That is a lot of patients in 15 years, and the results have been just as good as when we used 10 days as standard.

Acute sinusitis is another interesting story. The AAP guideline states: “The optimal duration of antimicrobial therapy for patients with acute bacterial sinusitis has not received systematic study. Recommendations based on  clinical observation varied widely, from 1- to 28 days (Pediatrics. 2013 Jul;132[1]:e262-80). The prior AAP guideline endorsed “antibiotic therapy be continued for 7 days after the patient becomes free of symptoms and signs (Pediatrics. 2001 Sep;108[3]:798-808). Our group reasoned that the etiology and pathogenesis of sinusitis and AOM are identical, involving ascension of a bacterial inoculum from the nasopharynx via the osteomeatal complex to the sinuses just like ascension of infection via the eustachian tube to the middle ear. Therefore, beginning 25 years ago, we began to treat all children with sinus infections for 5 days, including amoxicillin and amoxicillin/clavulanate, as well as various cephalosporins. Again, that is a lot of patients, and the results have been just as good as when we used 10 days as standard.

What about community-acquired pneumonia? The Infectious Disease Society of America (IDSA) guideline states: “Treatment courses of 10 days [of antibiotics] have been best studied, although shorter courses may be just as effective, particularly for mild disease managed on an outpatient basis” (Clin Infect Dis. 2011 Oct;53[7]:617-30). Our group reasoned that antibiotics reach higher levels in the lungs than they do in the closed space of the middle ear or sinuses. Therefore, beginning 25 years ago, we began to treat all children with bronchopneumonia and lobar pneumonia for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins and azithromycin. That is a lot of patients, and the results have been just as good as when we used 10 days as standard.

What about skin and soft tissue infections? The IDSA guideline states that the duration of treatment for impetigo is 7 days, for cellulitis is 5 days, and for furuncles and carbuncles no duration is stated, but they allow no antibiotics be used at all if the patient is not febrile and white blood cell count is not elevated after incision and drainage (Clin Infect Dis. 2014 Jul 15;59[2]:e10-52).

So what is the harm to longer courses of antibiotics? As I have written in this column recently, we have learned a lot about the importance of our gut microbiome. The resident flora of our gut modulates our immune system favorably. Disturbing our gut flora with antibiotics is potentially harmful because the antibiotics often kill many species of healthy gut flora and cause disequilibrium of the flora, resulting in diminished innate immunity responses. Shorter treatment courses with antibiotics cause less disturbance of the healthy gut flora.

The rest of the world cannot all be wrong and the United States all right regarding the duration of antibiotic treatment for common infections. Moreover, in an era of evidence-based medicine, it is necessary to make changes from tradition. The evidence is there to recommend that 5 days’ treatment become the standard for treatment with selected cephalosporins as approved by the FDA – for AOM, for sinusitis, for community-acquired pneumonia, and for skin and soft tissue infections.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Research Institute, Rochester (N.Y.) General Hospital. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero said that he had no relevant financial disclosures. Email him at pdnews@frontlinemedcom.com.

In the United States, we treat almost all infections for 10 days. Why? In France, most infections are treated for 8 days. In the U.K., most infections are treated for 5 days. In many other countries, infections are treated until symptomatic improvement occurs. Can everyone outside the United States be wrong? What is the evidence base for the various recommended durations? Moreover, what is the harm in treating for longer than necessary?

The U.S. tradition of 10 days’ treatment for infections arose from the 1940 trials of injectable penicillin for prevention of acute rheumatic fever in military recruits who had group A streptococcal pharyngitis. Injections of penicillin G mixed in peanut oil produced therapeutic levels of penicillin for about 3 days. Soldiers who received three sequential injections had the lowest occurrence of rheumatic fever; two injections were not as good and four injections did not add to the prevention rate. So three injections meant 9 days’ treatment; 9 days was rounded up to 10 days, and there you have it.

We have come a long way since the 1940s. For strep throat, we now have three approved antibiotics for 5 days’ treatment: cefdinir, cefpodoxime proxetil, and azithromycin, all evidence based and U.S. Food and Drug Administration approved. One large study was done in the 1980s with cefadroxil for 5 days, and that duration was as effective in strep eradication as was 10 days, but the company never pursued the 5-day indication.

The optimal duration of antibiotic treatment is generally considered to be 10 days in the United States, however, there is scant evidence base for that recommendation. The recent American Academy of Pediatrics/American Academy of Family Physicians guidelines endorse 10 days of treatment duration as the standard for most acute otitis media (AOM) (Pediatrics 2013;131[3]:e964-99), but acknowledge that shorter treatment regimens may be as effective. Specifically, the guideline states: “A 7-day course of oral antibiotic appears to be equally effective in children 2- to 5 years of age with mild to moderate AOM. For children 6 years and older with mild to moderate AOM symptoms, a 5- to 7-day course is adequate treatment.” A systematic analysis and a meta-analysis have concluded that 5 days’ duration of antibiotics is as effective as 10 days’ treatment for all children over age 2 years and only marginally inferior to 10 days for children under the age of 2 years old (Cochrane Database Syst Rev. 2010;[9]:CD001095).

Thirty years ago, our group and others began to do studies involving “double tympanocentesis,” where an ear tap was done at time of diagnosis and again 3-5 days later to prove bacterial cure for various antibiotics that were in trials. We learned that if the organism was sensitive to the antibiotic chosen, then it was dead by days 3-5. Most of the failures were due to resistant bacteria. So treating longer was not going to help. It was time to change the antibiotic if clinical improvement had not occurred. Our group published a study 15 years ago of 2,172 children comparing 5-, 7-, and 10-days’ treatment of AOM, and concluded that 5 days’ treatment was equivalent to 7- and 10-days of treatment for all ages unless the child had a perforated tympanic membrane or the child had been treated for AOM within the preceding month since recently treated AOM was associated with more frequent causation of AOM by resistant bacteria and with a continued inflamed middle ear mucosa (Otolaryngol Head Neck Surg. 2001 Apr;124[4]:381-7). Since then we have treated all children with ear infections for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins unless the eardrum had perforated or the child had a recurrent AOM within the prior 30 days. That is a lot of patients in 15 years, and the results have been just as good as when we used 10 days as standard.

Acute sinusitis is another interesting story. The AAP guideline states: “The optimal duration of antimicrobial therapy for patients with acute bacterial sinusitis has not received systematic study. Recommendations based on  clinical observation varied widely, from 1- to 28 days (Pediatrics. 2013 Jul;132[1]:e262-80). The prior AAP guideline endorsed “antibiotic therapy be continued for 7 days after the patient becomes free of symptoms and signs (Pediatrics. 2001 Sep;108[3]:798-808). Our group reasoned that the etiology and pathogenesis of sinusitis and AOM are identical, involving ascension of a bacterial inoculum from the nasopharynx via the osteomeatal complex to the sinuses just like ascension of infection via the eustachian tube to the middle ear. Therefore, beginning 25 years ago, we began to treat all children with sinus infections for 5 days, including amoxicillin and amoxicillin/clavulanate, as well as various cephalosporins. Again, that is a lot of patients, and the results have been just as good as when we used 10 days as standard.

What about community-acquired pneumonia? The Infectious Disease Society of America (IDSA) guideline states: “Treatment courses of 10 days [of antibiotics] have been best studied, although shorter courses may be just as effective, particularly for mild disease managed on an outpatient basis” (Clin Infect Dis. 2011 Oct;53[7]:617-30). Our group reasoned that antibiotics reach higher levels in the lungs than they do in the closed space of the middle ear or sinuses. Therefore, beginning 25 years ago, we began to treat all children with bronchopneumonia and lobar pneumonia for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins and azithromycin. That is a lot of patients, and the results have been just as good as when we used 10 days as standard.

What about skin and soft tissue infections? The IDSA guideline states that the duration of treatment for impetigo is 7 days, for cellulitis is 5 days, and for furuncles and carbuncles no duration is stated, but they allow no antibiotics be used at all if the patient is not febrile and white blood cell count is not elevated after incision and drainage (Clin Infect Dis. 2014 Jul 15;59[2]:e10-52).

So what is the harm to longer courses of antibiotics? As I have written in this column recently, we have learned a lot about the importance of our gut microbiome. The resident flora of our gut modulates our immune system favorably. Disturbing our gut flora with antibiotics is potentially harmful because the antibiotics often kill many species of healthy gut flora and cause disequilibrium of the flora, resulting in diminished innate immunity responses. Shorter treatment courses with antibiotics cause less disturbance of the healthy gut flora.

The rest of the world cannot all be wrong and the United States all right regarding the duration of antibiotic treatment for common infections. Moreover, in an era of evidence-based medicine, it is necessary to make changes from tradition. The evidence is there to recommend that 5 days’ treatment become the standard for treatment with selected cephalosporins as approved by the FDA – for AOM, for sinusitis, for community-acquired pneumonia, and for skin and soft tissue infections.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Research Institute, Rochester (N.Y.) General Hospital. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero said that he had no relevant financial disclosures. Email him at pdnews@frontlinemedcom.com.

In the United States, we treat almost all infections for 10 days. Why? In France, most infections are treated for 8 days. In the U.K., most infections are treated for 5 days. In many other countries, infections are treated until symptomatic improvement occurs. Can everyone outside the United States be wrong? What is the evidence base for the various recommended durations? Moreover, what is the harm in treating for longer than necessary?

The U.S. tradition of 10 days’ treatment for infections arose from the 1940 trials of injectable penicillin for prevention of acute rheumatic fever in military recruits who had group A streptococcal pharyngitis. Injections of penicillin G mixed in peanut oil produced therapeutic levels of penicillin for about 3 days. Soldiers who received three sequential injections had the lowest occurrence of rheumatic fever; two injections were not as good and four injections did not add to the prevention rate. So three injections meant 9 days’ treatment; 9 days was rounded up to 10 days, and there you have it.

We have come a long way since the 1940s. For strep throat, we now have three approved antibiotics for 5 days’ treatment: cefdinir, cefpodoxime proxetil, and azithromycin, all evidence based and U.S. Food and Drug Administration approved. One large study was done in the 1980s with cefadroxil for 5 days, and that duration was as effective in strep eradication as was 10 days, but the company never pursued the 5-day indication.

The optimal duration of antibiotic treatment is generally considered to be 10 days in the United States, however, there is scant evidence base for that recommendation. The recent American Academy of Pediatrics/American Academy of Family Physicians guidelines endorse 10 days of treatment duration as the standard for most acute otitis media (AOM) (Pediatrics 2013;131[3]:e964-99), but acknowledge that shorter treatment regimens may be as effective. Specifically, the guideline states: “A 7-day course of oral antibiotic appears to be equally effective in children 2- to 5 years of age with mild to moderate AOM. For children 6 years and older with mild to moderate AOM symptoms, a 5- to 7-day course is adequate treatment.” A systematic analysis and a meta-analysis have concluded that 5 days’ duration of antibiotics is as effective as 10 days’ treatment for all children over age 2 years and only marginally inferior to 10 days for children under the age of 2 years old (Cochrane Database Syst Rev. 2010;[9]:CD001095).

Thirty years ago, our group and others began to do studies involving “double tympanocentesis,” where an ear tap was done at time of diagnosis and again 3-5 days later to prove bacterial cure for various antibiotics that were in trials. We learned that if the organism was sensitive to the antibiotic chosen, then it was dead by days 3-5. Most of the failures were due to resistant bacteria. So treating longer was not going to help. It was time to change the antibiotic if clinical improvement had not occurred. Our group published a study 15 years ago of 2,172 children comparing 5-, 7-, and 10-days’ treatment of AOM, and concluded that 5 days’ treatment was equivalent to 7- and 10-days of treatment for all ages unless the child had a perforated tympanic membrane or the child had been treated for AOM within the preceding month since recently treated AOM was associated with more frequent causation of AOM by resistant bacteria and with a continued inflamed middle ear mucosa (Otolaryngol Head Neck Surg. 2001 Apr;124[4]:381-7). Since then we have treated all children with ear infections for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins unless the eardrum had perforated or the child had a recurrent AOM within the prior 30 days. That is a lot of patients in 15 years, and the results have been just as good as when we used 10 days as standard.

Acute sinusitis is another interesting story. The AAP guideline states: “The optimal duration of antimicrobial therapy for patients with acute bacterial sinusitis has not received systematic study. Recommendations based on  clinical observation varied widely, from 1- to 28 days (Pediatrics. 2013 Jul;132[1]:e262-80). The prior AAP guideline endorsed “antibiotic therapy be continued for 7 days after the patient becomes free of symptoms and signs (Pediatrics. 2001 Sep;108[3]:798-808). Our group reasoned that the etiology and pathogenesis of sinusitis and AOM are identical, involving ascension of a bacterial inoculum from the nasopharynx via the osteomeatal complex to the sinuses just like ascension of infection via the eustachian tube to the middle ear. Therefore, beginning 25 years ago, we began to treat all children with sinus infections for 5 days, including amoxicillin and amoxicillin/clavulanate, as well as various cephalosporins. Again, that is a lot of patients, and the results have been just as good as when we used 10 days as standard.

What about community-acquired pneumonia? The Infectious Disease Society of America (IDSA) guideline states: “Treatment courses of 10 days [of antibiotics] have been best studied, although shorter courses may be just as effective, particularly for mild disease managed on an outpatient basis” (Clin Infect Dis. 2011 Oct;53[7]:617-30). Our group reasoned that antibiotics reach higher levels in the lungs than they do in the closed space of the middle ear or sinuses. Therefore, beginning 25 years ago, we began to treat all children with bronchopneumonia and lobar pneumonia for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins and azithromycin. That is a lot of patients, and the results have been just as good as when we used 10 days as standard.

What about skin and soft tissue infections? The IDSA guideline states that the duration of treatment for impetigo is 7 days, for cellulitis is 5 days, and for furuncles and carbuncles no duration is stated, but they allow no antibiotics be used at all if the patient is not febrile and white blood cell count is not elevated after incision and drainage (Clin Infect Dis. 2014 Jul 15;59[2]:e10-52).

So what is the harm to longer courses of antibiotics? As I have written in this column recently, we have learned a lot about the importance of our gut microbiome. The resident flora of our gut modulates our immune system favorably. Disturbing our gut flora with antibiotics is potentially harmful because the antibiotics often kill many species of healthy gut flora and cause disequilibrium of the flora, resulting in diminished innate immunity responses. Shorter treatment courses with antibiotics cause less disturbance of the healthy gut flora.

The rest of the world cannot all be wrong and the United States all right regarding the duration of antibiotic treatment for common infections. Moreover, in an era of evidence-based medicine, it is necessary to make changes from tradition. The evidence is there to recommend that 5 days’ treatment become the standard for treatment with selected cephalosporins as approved by the FDA – for AOM, for sinusitis, for community-acquired pneumonia, and for skin and soft tissue infections.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Research Institute, Rochester (N.Y.) General Hospital. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero said that he had no relevant financial disclosures. Email him at pdnews@frontlinemedcom.com.

Who is in this video: Neil Kirschner, Ph.D., a clinical psychologist and the American College of Physicians’ senior associate for health policy and regulatory affairs; Dr. April Barbour, an associate professor of medicine and the director of general internal medicine and of the primary care residency program at George Washington University School of Medicine, Washington; Dr. James Griffith, the Leon M. Yochelson Professor of Psychiatry and Behavioral Sciences, and chair of psychiatry and psychosomatic medicine at George Washington University School of Medicine, Washington; Whitney McKnight, cohost and producer of Mental Health Consult.

Who is in this video: Neil Kirschner, Ph.D., a clinical psychologist and the American College of Physicians’ senior associate for health policy and regulatory affairs; Dr. April Barbour, an associate professor of medicine and the director of general internal medicine and of the primary care residency program at George Washington University School of Medicine, Washington; Dr. James Griffith, the Leon M. Yochelson Professor of Psychiatry and Behavioral Sciences, and chair of psychiatry and psychosomatic medicine at George Washington University School of Medicine, Washington; Whitney McKnight, cohost and producer of Mental Health Consult.

Who is in this video: Neil Kirschner, Ph.D., a clinical psychologist and the American College of Physicians’ senior associate for health policy and regulatory affairs; Dr. April Barbour, an associate professor of medicine and the director of general internal medicine and of the primary care residency program at George Washington University School of Medicine, Washington; Dr. James Griffith, the Leon M. Yochelson Professor of Psychiatry and Behavioral Sciences, and chair of psychiatry and psychosomatic medicine at George Washington University School of Medicine, Washington; Whitney McKnight, cohost and producer of Mental Health Consult.

To a psychiatrist, the idea of selling Prozac or Lexapro over the counter seems unthinkable. These medications, after all, carry a black box warning, and their adverse reactions can include the induction of mania as well as a usual laundry list of side effects.

Furthermore, used alone as a one-shot attempt to treat depression, they are not terribly effective. A trial of a single antidepressant will be effective about 30% of the time – about as often as a placebo – and it’s not until we try switching or augmentation strategies, or adding psychotherapy as part of comprehensive treatment, that we begin to see more robust success rates in the treatment of depression. Finally, there is the risk that a lay person might misdiagnose sadness or demoralization as depression and inappropriately treat himself.

With so much that can go wrong, why would I even ask such a provocative question?

So let me play devil’s advocate for a moment. We live in a country where 40,000 people a year die of suicide, and countless others are impaired or disabled with respect to their occupations and relationships because of depression and anxiety. And then there are those who are able to hide their symptoms, but live with psychic torment and suffering.

If you believe that the morbidity and mortality of psychiatric illness can be prevented with appropriate treatment, then you’re left to ask why people don’t get treatment for their psychiatric illnesses. The political mantra is that people don’t seek care because of stigma. Advocates for those with severe mental illnesses contend that people don’t seek treatment because they don’t believe they are ill. And then there are the difficult realities: It can be very hard to find a psychiatrist or even a nonphysician therapist. According to Dr. Thomas Insel, the former director of the National Institute of Mental Health, half the counties in this country have no mental health professionals at all. And while medical care of any type is expensive, psychiatry can be even more so in terms of out-of-pocket costs, because 45% of psychiatrists don’t participate with health insurance networks, compared with 89% of other physicians. Finally, some patients have had bad experiences with psychiatrists, or with the treatments that have been offered, and they are not open to the idea that there is a better experience to be had. So stigma, access to care, awareness that one has an illness, cost, and prior negative experiences all are deterrents to getting mental health treatment.

As it stands, most psychotropic medications are prescribed by primary care physicians. I don’t know what constitutes a psychiatric evaluation in these settings, but it’s not unusual for a patient to be given a year’s supply of medication without referrals for psychotherapy. I also don’t know how closely primary care physicians and nurse practitioners monitor patients, or if they warn them of the risk of mania or suicidal impulse. If medication trials are unsuccessful, or only partly helpful, do primary care physicians know how to switch and augment these agents? I’m sure this depends on the individual clinician, but chances are that some patients who seek treatment for psychiatric conditions are not treated adequately. Presumably, there is some evaluation and monitoring, and the patient has a prescriber to call if something goes wrong, so this is a better scenario than letting the patient pick up a bottle when she goes to buy deodorant.

The antipsychiatry lobby would howl at the idea of offering antidepressants over the counter. They would contend that selective serotonin reuptake inhibitors cause violence and disability, and such a move would cause the rates of suicide, homicide, and mass murders to soar. And those who feel that psychiatry has overextended its arm to embrace normal human reactions and sufferings such that every discomfort calls for a pill would be appalled at the idea that people could be self-diagnosing and self-treating either transient distresses or serious mental illnesses.

So what would be the upside to having over-the-counter SSRIs? For starters, if you believe that medication alone constitutes treatment for depression – and certainly it does for some people – then it would allow people with no access to at least begin the process of getting treatment. It also would allow people to begin medications anonymously, without concerns for stigma or the consequences of being identified as a psychiatric patient. Certainly, if medications were available over the counter, there would be a percentage of people who would take them and get tremendous relief from their symptoms. The question would be whether the good done for some would outweigh the harm done to others.

Patients are unlikely to read the inserts that come with medications, but perhaps OTC antidepressants could come with a video that would give instructions as to dosing, duration, risks, and when to seek help from a physician or in an emergency facility. The presentation could emphasize that while SSRIs can be very effective in treating depression and anxiety, other strategies are available, and people should see a psychiatrist for a complete evaluation. Perhaps patients who had a partial response would be more willing to seek out a mental health professional if they saw some benefit, much the way people go to their doctor when drugstore remedies don’t work for headaches or acid reflux. Furthermore, the availability of drugstore antidepressants might decrease the overall stigma of taking psychopharmacologic agents.

There are risks, but many people tolerate SSRIs. Perhaps over-the-counter antidepressants would save and improve lives; we just don’t know.

As I said above, I’m playing devil’s advocate. My last article asked the question of whether psychiatric treatment actually prevents suicide, and I concluded that it probably does. Yet SSRIs have not conclusively been shown to decrease suicide rates – the only medications known to do so are lithium and clozapine. Still, if patients are unable or unwilling to avail themselves of traditional psychiatric settings, perhaps it’s worth at least asking if some form of access is better than none at all. Society is wrestling with how to address the shortage of psychiatrists. Proposed solutions include telepsychiatry or having psychiatrists serve as consultants in settings where they don’t even meet the patients for whom they make medication recommendations. I haven’t heard anyone suggest that we let the patients try by themselves.

As a psychiatrist who treats patients with medications in combination with psychotherapy, it does seem like a strange question to ask; our patients deserve more than a bottle off a shelf. But before you get too concerned, let me assure you that I have no special connections at the Food and Drug Administration, and I’m just tossing the idea out as food for thought.

Dr. Miller is coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University, 2011).

To a psychiatrist, the idea of selling Prozac or Lexapro over the counter seems unthinkable. These medications, after all, carry a black box warning, and their adverse reactions can include the induction of mania as well as a usual laundry list of side effects.

Furthermore, used alone as a one-shot attempt to treat depression, they are not terribly effective. A trial of a single antidepressant will be effective about 30% of the time – about as often as a placebo – and it’s not until we try switching or augmentation strategies, or adding psychotherapy as part of comprehensive treatment, that we begin to see more robust success rates in the treatment of depression. Finally, there is the risk that a lay person might misdiagnose sadness or demoralization as depression and inappropriately treat himself.

With so much that can go wrong, why would I even ask such a provocative question?

So let me play devil’s advocate for a moment. We live in a country where 40,000 people a year die of suicide, and countless others are impaired or disabled with respect to their occupations and relationships because of depression and anxiety. And then there are those who are able to hide their symptoms, but live with psychic torment and suffering.

If you believe that the morbidity and mortality of psychiatric illness can be prevented with appropriate treatment, then you’re left to ask why people don’t get treatment for their psychiatric illnesses. The political mantra is that people don’t seek care because of stigma. Advocates for those with severe mental illnesses contend that people don’t seek treatment because they don’t believe they are ill. And then there are the difficult realities: It can be very hard to find a psychiatrist or even a nonphysician therapist. According to Dr. Thomas Insel, the former director of the National Institute of Mental Health, half the counties in this country have no mental health professionals at all. And while medical care of any type is expensive, psychiatry can be even more so in terms of out-of-pocket costs, because 45% of psychiatrists don’t participate with health insurance networks, compared with 89% of other physicians. Finally, some patients have had bad experiences with psychiatrists, or with the treatments that have been offered, and they are not open to the idea that there is a better experience to be had. So stigma, access to care, awareness that one has an illness, cost, and prior negative experiences all are deterrents to getting mental health treatment.

As it stands, most psychotropic medications are prescribed by primary care physicians. I don’t know what constitutes a psychiatric evaluation in these settings, but it’s not unusual for a patient to be given a year’s supply of medication without referrals for psychotherapy. I also don’t know how closely primary care physicians and nurse practitioners monitor patients, or if they warn them of the risk of mania or suicidal impulse. If medication trials are unsuccessful, or only partly helpful, do primary care physicians know how to switch and augment these agents? I’m sure this depends on the individual clinician, but chances are that some patients who seek treatment for psychiatric conditions are not treated adequately. Presumably, there is some evaluation and monitoring, and the patient has a prescriber to call if something goes wrong, so this is a better scenario than letting the patient pick up a bottle when she goes to buy deodorant.

The antipsychiatry lobby would howl at the idea of offering antidepressants over the counter. They would contend that selective serotonin reuptake inhibitors cause violence and disability, and such a move would cause the rates of suicide, homicide, and mass murders to soar. And those who feel that psychiatry has overextended its arm to embrace normal human reactions and sufferings such that every discomfort calls for a pill would be appalled at the idea that people could be self-diagnosing and self-treating either transient distresses or serious mental illnesses.

So what would be the upside to having over-the-counter SSRIs? For starters, if you believe that medication alone constitutes treatment for depression – and certainly it does for some people – then it would allow people with no access to at least begin the process of getting treatment. It also would allow people to begin medications anonymously, without concerns for stigma or the consequences of being identified as a psychiatric patient. Certainly, if medications were available over the counter, there would be a percentage of people who would take them and get tremendous relief from their symptoms. The question would be whether the good done for some would outweigh the harm done to others.

Patients are unlikely to read the inserts that come with medications, but perhaps OTC antidepressants could come with a video that would give instructions as to dosing, duration, risks, and when to seek help from a physician or in an emergency facility. The presentation could emphasize that while SSRIs can be very effective in treating depression and anxiety, other strategies are available, and people should see a psychiatrist for a complete evaluation. Perhaps patients who had a partial response would be more willing to seek out a mental health professional if they saw some benefit, much the way people go to their doctor when drugstore remedies don’t work for headaches or acid reflux. Furthermore, the availability of drugstore antidepressants might decrease the overall stigma of taking psychopharmacologic agents.

There are risks, but many people tolerate SSRIs. Perhaps over-the-counter antidepressants would save and improve lives; we just don’t know.

As I said above, I’m playing devil’s advocate. My last article asked the question of whether psychiatric treatment actually prevents suicide, and I concluded that it probably does. Yet SSRIs have not conclusively been shown to decrease suicide rates – the only medications known to do so are lithium and clozapine. Still, if patients are unable or unwilling to avail themselves of traditional psychiatric settings, perhaps it’s worth at least asking if some form of access is better than none at all. Society is wrestling with how to address the shortage of psychiatrists. Proposed solutions include telepsychiatry or having psychiatrists serve as consultants in settings where they don’t even meet the patients for whom they make medication recommendations. I haven’t heard anyone suggest that we let the patients try by themselves.

As a psychiatrist who treats patients with medications in combination with psychotherapy, it does seem like a strange question to ask; our patients deserve more than a bottle off a shelf. But before you get too concerned, let me assure you that I have no special connections at the Food and Drug Administration, and I’m just tossing the idea out as food for thought.

Dr. Miller is coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University, 2011).

To a psychiatrist, the idea of selling Prozac or Lexapro over the counter seems unthinkable. These medications, after all, carry a black box warning, and their adverse reactions can include the induction of mania as well as a usual laundry list of side effects.

Furthermore, used alone as a one-shot attempt to treat depression, they are not terribly effective. A trial of a single antidepressant will be effective about 30% of the time – about as often as a placebo – and it’s not until we try switching or augmentation strategies, or adding psychotherapy as part of comprehensive treatment, that we begin to see more robust success rates in the treatment of depression. Finally, there is the risk that a lay person might misdiagnose sadness or demoralization as depression and inappropriately treat himself.

With so much that can go wrong, why would I even ask such a provocative question?

So let me play devil’s advocate for a moment. We live in a country where 40,000 people a year die of suicide, and countless others are impaired or disabled with respect to their occupations and relationships because of depression and anxiety. And then there are those who are able to hide their symptoms, but live with psychic torment and suffering.

If you believe that the morbidity and mortality of psychiatric illness can be prevented with appropriate treatment, then you’re left to ask why people don’t get treatment for their psychiatric illnesses. The political mantra is that people don’t seek care because of stigma. Advocates for those with severe mental illnesses contend that people don’t seek treatment because they don’t believe they are ill. And then there are the difficult realities: It can be very hard to find a psychiatrist or even a nonphysician therapist. According to Dr. Thomas Insel, the former director of the National Institute of Mental Health, half the counties in this country have no mental health professionals at all. And while medical care of any type is expensive, psychiatry can be even more so in terms of out-of-pocket costs, because 45% of psychiatrists don’t participate with health insurance networks, compared with 89% of other physicians. Finally, some patients have had bad experiences with psychiatrists, or with the treatments that have been offered, and they are not open to the idea that there is a better experience to be had. So stigma, access to care, awareness that one has an illness, cost, and prior negative experiences all are deterrents to getting mental health treatment.

As it stands, most psychotropic medications are prescribed by primary care physicians. I don’t know what constitutes a psychiatric evaluation in these settings, but it’s not unusual for a patient to be given a year’s supply of medication without referrals for psychotherapy. I also don’t know how closely primary care physicians and nurse practitioners monitor patients, or if they warn them of the risk of mania or suicidal impulse. If medication trials are unsuccessful, or only partly helpful, do primary care physicians know how to switch and augment these agents? I’m sure this depends on the individual clinician, but chances are that some patients who seek treatment for psychiatric conditions are not treated adequately. Presumably, there is some evaluation and monitoring, and the patient has a prescriber to call if something goes wrong, so this is a better scenario than letting the patient pick up a bottle when she goes to buy deodorant.

The antipsychiatry lobby would howl at the idea of offering antidepressants over the counter. They would contend that selective serotonin reuptake inhibitors cause violence and disability, and such a move would cause the rates of suicide, homicide, and mass murders to soar. And those who feel that psychiatry has overextended its arm to embrace normal human reactions and sufferings such that every discomfort calls for a pill would be appalled at the idea that people could be self-diagnosing and self-treating either transient distresses or serious mental illnesses.

So what would be the upside to having over-the-counter SSRIs? For starters, if you believe that medication alone constitutes treatment for depression – and certainly it does for some people – then it would allow people with no access to at least begin the process of getting treatment. It also would allow people to begin medications anonymously, without concerns for stigma or the consequences of being identified as a psychiatric patient. Certainly, if medications were available over the counter, there would be a percentage of people who would take them and get tremendous relief from their symptoms. The question would be whether the good done for some would outweigh the harm done to others.

Patients are unlikely to read the inserts that come with medications, but perhaps OTC antidepressants could come with a video that would give instructions as to dosing, duration, risks, and when to seek help from a physician or in an emergency facility. The presentation could emphasize that while SSRIs can be very effective in treating depression and anxiety, other strategies are available, and people should see a psychiatrist for a complete evaluation. Perhaps patients who had a partial response would be more willing to seek out a mental health professional if they saw some benefit, much the way people go to their doctor when drugstore remedies don’t work for headaches or acid reflux. Furthermore, the availability of drugstore antidepressants might decrease the overall stigma of taking psychopharmacologic agents.

There are risks, but many people tolerate SSRIs. Perhaps over-the-counter antidepressants would save and improve lives; we just don’t know.

As I said above, I’m playing devil’s advocate. My last article asked the question of whether psychiatric treatment actually prevents suicide, and I concluded that it probably does. Yet SSRIs have not conclusively been shown to decrease suicide rates – the only medications known to do so are lithium and clozapine. Still, if patients are unable or unwilling to avail themselves of traditional psychiatric settings, perhaps it’s worth at least asking if some form of access is better than none at all. Society is wrestling with how to address the shortage of psychiatrists. Proposed solutions include telepsychiatry or having psychiatrists serve as consultants in settings where they don’t even meet the patients for whom they make medication recommendations. I haven’t heard anyone suggest that we let the patients try by themselves.

As a psychiatrist who treats patients with medications in combination with psychotherapy, it does seem like a strange question to ask; our patients deserve more than a bottle off a shelf. But before you get too concerned, let me assure you that I have no special connections at the Food and Drug Administration, and I’m just tossing the idea out as food for thought.

Dr. Miller is coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University, 2011).

People in this video: Whitney McKnight, cohost and producer of Mental Health Consult; Dr. Lorenzo Norris, editorial board member of Clinical Psychiatry News and cohost of Mental Health Consult, and an assistant professor of psychiatry and behavioral sciences, assistant dean of student affairs, and the medical director of psychiatric and behavioral services at George Washington University Hospital, Washington; Dr. Lillian Beard, pediatrician with Children’s National Hospital Network, Washington, and a Pediatric News editorial board member; Dr. David Pickar, adjunct professor of psychiatry at Johns Hopkins University School of Medicine in Baltimore and at the Uniformed Services University of the Health Sciences in Bethesda, Md.

Dr. Pickar: Psychosis is the hallmark of serious mental illness, whether it's schizophrenia, severe bipolar, or psychosis otherwise. It is one of the great tragedies of our medical system, and I'll come back to the primary doc who's out there. I want to talk to you about this. It is a tragedy. Whitney knows, I put together a little documentary, The Realities of Serious Mental Illness. I just couldn't stand the lack of information.

They're very quick to report the violence, and I know a lot about the violence. I worry about it all the time. There's a huge debate between civil liberties and safety that's going on in serious mental illness. Regardless, knowing about it is enormously important for all docs. More patients with serious mental illness, by far, are in jails than they are in mental hospitals. There is nothing for them. You talk about collaborative care.
 
Whitney: On the team in the primary care setting, who's treating what?

Dr. Pickar: I'm talking now myself. A family member brings in an 18-year-old to evaluate. Okay? I'm glad to see it. Of course, I've been around a while. I spent decades as a scientist in schizophrenia. I just close my eyes and hope that I'm not seeing a first break for a seriously mental ill patient. Not that we can't treat it. Not that we can't help, but I know what's entailed. Not unlike seeing an oncology presentation. We're there. We're docs. You don't give up on it, but you know what's ahead for that family.

What's fascinating is many of the first breaks occur, not necessarily quietly, but can be a little insidious. They can be brought to the primary care. It is not uncommon. “My 16-year-old's not doing well. I can't get him up.” But really, what's going on? The primary care doc needs to have a consciousness of that. Let me just say this: First things about serious mental illness, particularly in schizophrenia, 1% of the population has it. That makes it a very common disorder.

People in this video: Whitney McKnight, cohost and producer of Mental Health Consult; Dr. Lorenzo Norris, editorial board member of Clinical Psychiatry News and cohost of Mental Health Consult, and an assistant professor of psychiatry and behavioral sciences, assistant dean of student affairs, and the medical director of psychiatric and behavioral services at George Washington University Hospital, Washington; Dr. Lillian Beard, pediatrician with Children’s National Hospital Network, Washington, and a Pediatric News editorial board member; Dr. David Pickar, adjunct professor of psychiatry at Johns Hopkins University School of Medicine in Baltimore and at the Uniformed Services University of the Health Sciences in Bethesda, Md.

Dr. Pickar: Psychosis is the hallmark of serious mental illness, whether it's schizophrenia, severe bipolar, or psychosis otherwise. It is one of the great tragedies of our medical system, and I'll come back to the primary doc who's out there. I want to talk to you about this. It is a tragedy. Whitney knows, I put together a little documentary, The Realities of Serious Mental Illness. I just couldn't stand the lack of information.

They're very quick to report the violence, and I know a lot about the violence. I worry about it all the time. There's a huge debate between civil liberties and safety that's going on in serious mental illness. Regardless, knowing about it is enormously important for all docs. More patients with serious mental illness, by far, are in jails than they are in mental hospitals. There is nothing for them. You talk about collaborative care.
 
Whitney: On the team in the primary care setting, who's treating what?

Dr. Pickar: I'm talking now myself. A family member brings in an 18-year-old to evaluate. Okay? I'm glad to see it. Of course, I've been around a while. I spent decades as a scientist in schizophrenia. I just close my eyes and hope that I'm not seeing a first break for a seriously mental ill patient. Not that we can't treat it. Not that we can't help, but I know what's entailed. Not unlike seeing an oncology presentation. We're there. We're docs. You don't give up on it, but you know what's ahead for that family.

What's fascinating is many of the first breaks occur, not necessarily quietly, but can be a little insidious. They can be brought to the primary care. It is not uncommon. “My 16-year-old's not doing well. I can't get him up.” But really, what's going on? The primary care doc needs to have a consciousness of that. Let me just say this: First things about serious mental illness, particularly in schizophrenia, 1% of the population has it. That makes it a very common disorder.

People in this video: Whitney McKnight, cohost and producer of Mental Health Consult; Dr. Lorenzo Norris, editorial board member of Clinical Psychiatry News and cohost of Mental Health Consult, and an assistant professor of psychiatry and behavioral sciences, assistant dean of student affairs, and the medical director of psychiatric and behavioral services at George Washington University Hospital, Washington; Dr. Lillian Beard, pediatrician with Children’s National Hospital Network, Washington, and a Pediatric News editorial board member; Dr. David Pickar, adjunct professor of psychiatry at Johns Hopkins University School of Medicine in Baltimore and at the Uniformed Services University of the Health Sciences in Bethesda, Md.

Dr. Pickar: Psychosis is the hallmark of serious mental illness, whether it's schizophrenia, severe bipolar, or psychosis otherwise. It is one of the great tragedies of our medical system, and I'll come back to the primary doc who's out there. I want to talk to you about this. It is a tragedy. Whitney knows, I put together a little documentary, The Realities of Serious Mental Illness. I just couldn't stand the lack of information.

They're very quick to report the violence, and I know a lot about the violence. I worry about it all the time. There's a huge debate between civil liberties and safety that's going on in serious mental illness. Regardless, knowing about it is enormously important for all docs. More patients with serious mental illness, by far, are in jails than they are in mental hospitals. There is nothing for them. You talk about collaborative care.
 
Whitney: On the team in the primary care setting, who's treating what?

Dr. Pickar: I'm talking now myself. A family member brings in an 18-year-old to evaluate. Okay? I'm glad to see it. Of course, I've been around a while. I spent decades as a scientist in schizophrenia. I just close my eyes and hope that I'm not seeing a first break for a seriously mental ill patient. Not that we can't treat it. Not that we can't help, but I know what's entailed. Not unlike seeing an oncology presentation. We're there. We're docs. You don't give up on it, but you know what's ahead for that family.

What's fascinating is many of the first breaks occur, not necessarily quietly, but can be a little insidious. They can be brought to the primary care. It is not uncommon. “My 16-year-old's not doing well. I can't get him up.” But really, what's going on? The primary care doc needs to have a consciousness of that. Let me just say this: First things about serious mental illness, particularly in schizophrenia, 1% of the population has it. That makes it a very common disorder.

SAN DIEGO – The Neck Disability Index–10 did not perform as well as the Neck Disability Index–5 in assessing patient-reported outcomes in cervical spine patients – and neither was as good as the PROMIS physical function domain delivered by computerized adaptive testing.

Those are the key findings from an analysis of data from more than 500 cervical spine patients treated at University of Utah Health Care in Salt Lake City.

“Previous studies by us and others have shown problems with the NDI [Neck Disability Index] as it is commonly administered” in 10 questions, lead study author Dr. Darrel S. Brodke said in an interview in advance of the annual meeting of the Cervical Spine Research Society. “It has a very poor floor effect, meaning that it does not differentiate between minimally disabled patients, and the scores cannot be appropriately handled with the kinds of statistics that we normally use – though because few of us know this, we still use it as a standard parametric measure.”

In what he said is the first study of its kind, Dr. Brodke, professor of orthopedics at the University of Utah, and his associates set out to compare the psychometric performance of the National Institutes of Health–funded PROMIS (Patient Reported Outcomes Measurement Information System) physical function (PF) domain, administered by computerized adaptive testing, with the standard NDI-10, the NDI-5, and the 36-Item Short Form physical function domain (SF-36 PFD).

In all, 566 patients completed the NDI and PROMIS PF computerized adaptive testing assessments, while 490 also completed the SF-36 PFD.

On average, the NDI-10 took the longest to complete (10 questions in a mean of 183 seconds), followed by the SF-36 PFD (5 questions in a mean of 123 seconds), the NDI-5 (5 questions in a mean of 99 seconds), and the PROMIS PF computerized adaptive testing (between 4 and 12 questions in a mean of 62 seconds).

The psychometric properties of the PROMIS PF computerized adaptive testing were superior to the other outcome measurement tools studied, Dr. Brodke reported. Specifically, the ceiling and floor effects were “excellent” for the PROMIS PF computerized adaptive testing (1.94% and 4.06%, respectively), while the ceiling effects were “fine” for the NDI-10 (4.77%), NDI-5 (7.60%), and SF-36 PFD (11.84%), he said.

However, the floor effects of these three instruments were poor (45.58%, 48.59% and 21.55%, respectively). “The NDI-10 also has the additional challenge of extremely poor raw score to measure correlation,” the researchers noted in their abstract.

“The legacy scale scores significantly predicted the PROMIS PF CAT scores (P less than .0001), with fair correlation for the PF CAT and NDI-10 (0.53) and good correlation of PF CAT and SF-36 PFD (0.62), allowing use of conversion equations to predict scores, which were generated,” the investigators explained.

PROMIS PF computerized adaptive testing “does much better than the NDI or the SF-36 physical function domain at characterizing patients’ physical function, with much better coverage,” Dr. Brodke said. “Not only this, but it is also much faster to fill out, so less burdensome to the patient and the clinic.”

One limitation of the study is that the researchers did not measure the responsiveness aspect of PROMIS performance. “We did not have enough pre- and posttreatment scores to do this measurement yet,” Dr. Brodke said. “The other thing is that minimum clinically important difference [MCID] is not yet worked out for PROMIS in this patient population, though we can infer an MCID as one-half of a standard deviation. More to come in future studies.”

Dr. Brodke reported having no financial disclosures.

dbrunk@frontlinemedcom.com

SAN DIEGO – The Neck Disability Index–10 did not perform as well as the Neck Disability Index–5 in assessing patient-reported outcomes in cervical spine patients – and neither was as good as the PROMIS physical function domain delivered by computerized adaptive testing.

Those are the key findings from an analysis of data from more than 500 cervical spine patients treated at University of Utah Health Care in Salt Lake City.

“Previous studies by us and others have shown problems with the NDI [Neck Disability Index] as it is commonly administered” in 10 questions, lead study author Dr. Darrel S. Brodke said in an interview in advance of the annual meeting of the Cervical Spine Research Society. “It has a very poor floor effect, meaning that it does not differentiate between minimally disabled patients, and the scores cannot be appropriately handled with the kinds of statistics that we normally use – though because few of us know this, we still use it as a standard parametric measure.”

In what he said is the first study of its kind, Dr. Brodke, professor of orthopedics at the University of Utah, and his associates set out to compare the psychometric performance of the National Institutes of Health–funded PROMIS (Patient Reported Outcomes Measurement Information System) physical function (PF) domain, administered by computerized adaptive testing, with the standard NDI-10, the NDI-5, and the 36-Item Short Form physical function domain (SF-36 PFD).

In all, 566 patients completed the NDI and PROMIS PF computerized adaptive testing assessments, while 490 also completed the SF-36 PFD.

On average, the NDI-10 took the longest to complete (10 questions in a mean of 183 seconds), followed by the SF-36 PFD (5 questions in a mean of 123 seconds), the NDI-5 (5 questions in a mean of 99 seconds), and the PROMIS PF computerized adaptive testing (between 4 and 12 questions in a mean of 62 seconds).

The psychometric properties of the PROMIS PF computerized adaptive testing were superior to the other outcome measurement tools studied, Dr. Brodke reported. Specifically, the ceiling and floor effects were “excellent” for the PROMIS PF computerized adaptive testing (1.94% and 4.06%, respectively), while the ceiling effects were “fine” for the NDI-10 (4.77%), NDI-5 (7.60%), and SF-36 PFD (11.84%), he said.

However, the floor effects of these three instruments were poor (45.58%, 48.59% and 21.55%, respectively). “The NDI-10 also has the additional challenge of extremely poor raw score to measure correlation,” the researchers noted in their abstract.

“The legacy scale scores significantly predicted the PROMIS PF CAT scores (P less than .0001), with fair correlation for the PF CAT and NDI-10 (0.53) and good correlation of PF CAT and SF-36 PFD (0.62), allowing use of conversion equations to predict scores, which were generated,” the investigators explained.

PROMIS PF computerized adaptive testing “does much better than the NDI or the SF-36 physical function domain at characterizing patients’ physical function, with much better coverage,” Dr. Brodke said. “Not only this, but it is also much faster to fill out, so less burdensome to the patient and the clinic.”

One limitation of the study is that the researchers did not measure the responsiveness aspect of PROMIS performance. “We did not have enough pre- and posttreatment scores to do this measurement yet,” Dr. Brodke said. “The other thing is that minimum clinically important difference [MCID] is not yet worked out for PROMIS in this patient population, though we can infer an MCID as one-half of a standard deviation. More to come in future studies.”

Dr. Brodke reported having no financial disclosures.

dbrunk@frontlinemedcom.com

SAN DIEGO – The Neck Disability Index–10 did not perform as well as the Neck Disability Index–5 in assessing patient-reported outcomes in cervical spine patients – and neither was as good as the PROMIS physical function domain delivered by computerized adaptive testing.

Those are the key findings from an analysis of data from more than 500 cervical spine patients treated at University of Utah Health Care in Salt Lake City.

“Previous studies by us and others have shown problems with the NDI [Neck Disability Index] as it is commonly administered” in 10 questions, lead study author Dr. Darrel S. Brodke said in an interview in advance of the annual meeting of the Cervical Spine Research Society. “It has a very poor floor effect, meaning that it does not differentiate between minimally disabled patients, and the scores cannot be appropriately handled with the kinds of statistics that we normally use – though because few of us know this, we still use it as a standard parametric measure.”

In what he said is the first study of its kind, Dr. Brodke, professor of orthopedics at the University of Utah, and his associates set out to compare the psychometric performance of the National Institutes of Health–funded PROMIS (Patient Reported Outcomes Measurement Information System) physical function (PF) domain, administered by computerized adaptive testing, with the standard NDI-10, the NDI-5, and the 36-Item Short Form physical function domain (SF-36 PFD).

In all, 566 patients completed the NDI and PROMIS PF computerized adaptive testing assessments, while 490 also completed the SF-36 PFD.

On average, the NDI-10 took the longest to complete (10 questions in a mean of 183 seconds), followed by the SF-36 PFD (5 questions in a mean of 123 seconds), the NDI-5 (5 questions in a mean of 99 seconds), and the PROMIS PF computerized adaptive testing (between 4 and 12 questions in a mean of 62 seconds).

The psychometric properties of the PROMIS PF computerized adaptive testing were superior to the other outcome measurement tools studied, Dr. Brodke reported. Specifically, the ceiling and floor effects were “excellent” for the PROMIS PF computerized adaptive testing (1.94% and 4.06%, respectively), while the ceiling effects were “fine” for the NDI-10 (4.77%), NDI-5 (7.60%), and SF-36 PFD (11.84%), he said.

However, the floor effects of these three instruments were poor (45.58%, 48.59% and 21.55%, respectively). “The NDI-10 also has the additional challenge of extremely poor raw score to measure correlation,” the researchers noted in their abstract.

“The legacy scale scores significantly predicted the PROMIS PF CAT scores (P less than .0001), with fair correlation for the PF CAT and NDI-10 (0.53) and good correlation of PF CAT and SF-36 PFD (0.62), allowing use of conversion equations to predict scores, which were generated,” the investigators explained.

PROMIS PF computerized adaptive testing “does much better than the NDI or the SF-36 physical function domain at characterizing patients’ physical function, with much better coverage,” Dr. Brodke said. “Not only this, but it is also much faster to fill out, so less burdensome to the patient and the clinic.”

One limitation of the study is that the researchers did not measure the responsiveness aspect of PROMIS performance. “We did not have enough pre- and posttreatment scores to do this measurement yet,” Dr. Brodke said. “The other thing is that minimum clinically important difference [MCID] is not yet worked out for PROMIS in this patient population, though we can infer an MCID as one-half of a standard deviation. More to come in future studies.”

Dr. Brodke reported having no financial disclosures.

dbrunk@frontlinemedcom.com