As our nation faces an unprecedented opioid epidemic, mental health clinicians must communicate to patients options for treatment for opioid use disorders (OUDs). A small subset of patients who suffer from an OUD will be consistently motivated in their willingness to accept and fully engage in medically assisted treatment (MAT). However, most patients will display fluctuating degrees of intrinsic motivation in their perceived abilities, needs, and desires for MAT. As of 2017, the MAT agents that are approved for use in OUD by the Food and Drug Administration are methadone, buprenorphine, and naltrexone.

An obvious first step in treating these patients is to forge a therapeutic alliance that allows the patient to feel comfortable expressing myriad emotions, including shame, sadness, fear, anger, guilt, relief, hopefulness, and hopelessness. It is important for the clinician to have a nonjudgmental, kind, open, and empathic approach. We also must be able to specifically empathize with the ambivalence many patients feel regarding MAT. This column will review common questions and concerns that patients voice when contemplating the use of the long-acting injectable naltrexone (Vivitrol). In addition, this article will attempt to provide clinicians with possible responses to these questions, and aim to increase the likelihood that patients will be willing to accept treatment with Vivitrol.

Patient: “If I’m sober, then I should be completely sober, and that includes abstaining from Vivitrol.”

Here, this patient has expressed his/her point of view on what it means to be sober. This view is not uncommon. The clinician should explore the origin of this belief. This particular response may be internalized from an experience in a 12-step program. Or it may be a personal feeling. Engage in a conversation about what sobriety means to the patient, his or her personal goals, and thoughts related to how opiates might interfere with these goals. Clinicians should resist the urge to persuade a patient to use Vivitrol, regardless of how strongly the clinician feels about its effectiveness, in order to address the patient’s ambivalence. Join in with the patient to acknowledge and shed light on his or her perspective and ultimately support a well-informed decision that incorporates a patient’s individual values.
 

Patient: “Others will judge me and say that I can’t handle life without Vivitrol and I need a crutch.”

The truth is, others may think this. Clinicians should acknowledge that the influential people in the lives of our patients may very well be judgmental. But it is a potential barrier for this patient to be too concerned with others’ reaction to Vivitrol. Stay with the patient’s concern about being judged in order to move into a discussion about ways to tolerate that response. Maybe this is a time to ask whether it would be helpful to educate family members about Vivitrol or to problem-solve ways to handle interactions with others when they say this. It also might be a time to explore questions such as “Why is needing a crutch a sign of weakness to you?” Take a moment to understand the patient’s feelings about using “crutches.” This may open up the dialogue and the potential for seeing Vivitrol as a helpful resource rather than a sign of weakness.

Patient: “If I am doing so well, why introduce another medication?”

That is a valid question, especially if the patient has experienced real change and doesn’t see a need to mix things up. You can tell them that they may be right. However, this also is an opportunity to engage in a meaningful discussion with the patient about the nature of addiction and the nature of motivation. It may be helpful to review the triggers and patterns of use for this particular patient. Remind him or her that motivation to stay sober is fluid. People in the process of change typically are in regular dialogue with themselves about what they want, why they want it, and what they need to do. It is a natural part of the process to sometimes favor sobriety, while other times want to use. Vivitrol is ONE way to manage the relationship between these fluctuations and the desire to act on urges. This may be an appropriate time to tell the patient about other patients’ experiences with Vivitrol and how they experienced relief from not having to work through the costs and benefits of using on a constant basis.
 

Patient: “I feel controlled by Vivitrol, and it brings up a lot of emotions for me.”

For the most part, Vivitrol will remove the person’s day-to-day participation in their decision to use drugs. This is unsettling for many of our patients who find that using a substance of their own volition makes them feel more in control than does taking a prescribed medicine. The decision to use Vivitrol to treat their addiction is asking patients to think ahead and face what comes up day to day in ways they may not have. Clients can experience fear and sadness when attempting to manage life without the “escape hatch.” It’s natural to want to fight against any feelings of being controlled. To work through ambivalence, allow the patient to air these concerns, acknowledge that feeling controlled understandably is an uncomfortable experience, and then move into ways the patient may see Vivitrol as giving them more control. It is in this kind of conversation about the pros and cons that we can help a patient recognize what feels “wise” in the long term.

Patient: “If I take Vivitrol, I could imagine using many more opioids to override the blockade.”

This thought is a kind of hopeless, automatic one, such as “This won’t work for me,” or “I will just use on it.” We can remind our patient that a thought is simply a thought. Mindfulness can be used to help this patient identify and label his/her thoughts. The task is then to figure out whether it is wise to act on those thoughts. It is crucial to be able to monitor and track this kind of thinking to help a patient identify and manage cravings. These thoughts will happen, but the behavior does not have to follow. In dialectical behavior therapy, we help patients identify thoughts that come mostly from emotions, which are, for the most part, about having short-term relief rather than thoughts that are more balanced by emotion and reason. We call the latter kinds of thoughts “wise mind”; they are more focused on long-term goals. Clinicians should help the patient discern the difference between these different types of thoughts. Remember, if the patients are sitting in your office, there must have been some “wise mind thinking” that led them there, and you should highlight and explore why they made that choice in the first place.
 

Patient: “I want to have the ability to use opioids if things get really bad.”

Opioids can become a source of security and a reliable resource that doesn’t fail the patient when he or she is struggling. Most of the time, patients have gotten to a place in which opioids are the only coping skill they have to manage life’s difficulties. These clients need to relearn alternative coping skills. Using Vivitrol gives them the ability to be sober enough to practice distress tolerance skills and realize the benefits of not using opioids. Learning how to distract, soothe, and use relaxation strategies are the only ways they are going to be able to build a satisfying life again without substance use. If we can hold up the dilemma facing this person by saying “On the one hand, you are scared not to have your usual go-to; and on the other hand, you want things to change.” It may be helpful to have an in-depth discussion of what patients imagine might happen if they don’t have opioids to fall back on. This discussion may uncover the patients’ lack of confidence about being able to cope and a way to introduce some of the alternative coping strategies. It also may leave them with some concrete ways to manage the difficult feelings they are experiencing.
 

Patient: “What if I get in an accident and really need opioids?”

Some patients who have developed a dependence on opioids did so as a result of a past prescription for pain medication. They know very well the relationship between opioids and pain relief and the concern that they won’t have this option may be a real obstacle for them. Clinicians are in a position here to explain that, in most cases, patients can be treated with alternatives to opiate medication such as regional analgesia, nonopioid analgesics, and general anesthesia. In an emergency situation, a trained anesthesia provider is able to reverse the Vivitrol blockade so that the client can receive adequate pain management.
 

Patient: “I’m worried about side effects … ”

The most common side effects of Vivitrol are headache, nausea, somnolence, and vomiting. A serious but very rare complication is hepatocellular injury, but this is really only seen at extremely high doses of naltrexone (five times the approved dosage). If the patient is pregnant or planning pregnancy, she should consider alternative relapse-prevention medications, such as buprenorphine or methadone. If the patient has a proven allergy to naltrexone, polylactide-co-glycolide, carboxymethylcellulose, or any other component of the injection, Vivitrol should be avoided. As for the injection site, the client may experience some pain, tenderness, swelling, bruising. In very few cases, the site reaction can be severe. Again, here is an opportunity for a valuation of pros and cons of both continued opioid use and a Vivitrol trial.
 

Dr. Ascher is a board-certified general and addiction psychiatrist who serves as a clinical assistant professor in psychiatry at the University of Pennsylvania, Philadelphia, and is in private practice. Dr. Rosof is a clinical psychologist in Philadelphia with a specialty in addiction and extensive training in motivational approaches. Dr. Schack is a clinical psychologist who serves as an expert consultant with the Center for Motivation and Change and is private practice in Philadelphia and New York City. None of them have conflicts of interest to disclose.

As our nation faces an unprecedented opioid epidemic, mental health clinicians must communicate to patients options for treatment for opioid use disorders (OUDs). A small subset of patients who suffer from an OUD will be consistently motivated in their willingness to accept and fully engage in medically assisted treatment (MAT). However, most patients will display fluctuating degrees of intrinsic motivation in their perceived abilities, needs, and desires for MAT. As of 2017, the MAT agents that are approved for use in OUD by the Food and Drug Administration are methadone, buprenorphine, and naltrexone.

An obvious first step in treating these patients is to forge a therapeutic alliance that allows the patient to feel comfortable expressing myriad emotions, including shame, sadness, fear, anger, guilt, relief, hopefulness, and hopelessness. It is important for the clinician to have a nonjudgmental, kind, open, and empathic approach. We also must be able to specifically empathize with the ambivalence many patients feel regarding MAT. This column will review common questions and concerns that patients voice when contemplating the use of the long-acting injectable naltrexone (Vivitrol). In addition, this article will attempt to provide clinicians with possible responses to these questions, and aim to increase the likelihood that patients will be willing to accept treatment with Vivitrol.

Patient: “If I’m sober, then I should be completely sober, and that includes abstaining from Vivitrol.”

Here, this patient has expressed his/her point of view on what it means to be sober. This view is not uncommon. The clinician should explore the origin of this belief. This particular response may be internalized from an experience in a 12-step program. Or it may be a personal feeling. Engage in a conversation about what sobriety means to the patient, his or her personal goals, and thoughts related to how opiates might interfere with these goals. Clinicians should resist the urge to persuade a patient to use Vivitrol, regardless of how strongly the clinician feels about its effectiveness, in order to address the patient’s ambivalence. Join in with the patient to acknowledge and shed light on his or her perspective and ultimately support a well-informed decision that incorporates a patient’s individual values.
 

Patient: “Others will judge me and say that I can’t handle life without Vivitrol and I need a crutch.”

The truth is, others may think this. Clinicians should acknowledge that the influential people in the lives of our patients may very well be judgmental. But it is a potential barrier for this patient to be too concerned with others’ reaction to Vivitrol. Stay with the patient’s concern about being judged in order to move into a discussion about ways to tolerate that response. Maybe this is a time to ask whether it would be helpful to educate family members about Vivitrol or to problem-solve ways to handle interactions with others when they say this. It also might be a time to explore questions such as “Why is needing a crutch a sign of weakness to you?” Take a moment to understand the patient’s feelings about using “crutches.” This may open up the dialogue and the potential for seeing Vivitrol as a helpful resource rather than a sign of weakness.

Patient: “If I am doing so well, why introduce another medication?”

That is a valid question, especially if the patient has experienced real change and doesn’t see a need to mix things up. You can tell them that they may be right. However, this also is an opportunity to engage in a meaningful discussion with the patient about the nature of addiction and the nature of motivation. It may be helpful to review the triggers and patterns of use for this particular patient. Remind him or her that motivation to stay sober is fluid. People in the process of change typically are in regular dialogue with themselves about what they want, why they want it, and what they need to do. It is a natural part of the process to sometimes favor sobriety, while other times want to use. Vivitrol is ONE way to manage the relationship between these fluctuations and the desire to act on urges. This may be an appropriate time to tell the patient about other patients’ experiences with Vivitrol and how they experienced relief from not having to work through the costs and benefits of using on a constant basis.
 

Patient: “I feel controlled by Vivitrol, and it brings up a lot of emotions for me.”

For the most part, Vivitrol will remove the person’s day-to-day participation in their decision to use drugs. This is unsettling for many of our patients who find that using a substance of their own volition makes them feel more in control than does taking a prescribed medicine. The decision to use Vivitrol to treat their addiction is asking patients to think ahead and face what comes up day to day in ways they may not have. Clients can experience fear and sadness when attempting to manage life without the “escape hatch.” It’s natural to want to fight against any feelings of being controlled. To work through ambivalence, allow the patient to air these concerns, acknowledge that feeling controlled understandably is an uncomfortable experience, and then move into ways the patient may see Vivitrol as giving them more control. It is in this kind of conversation about the pros and cons that we can help a patient recognize what feels “wise” in the long term.

Patient: “If I take Vivitrol, I could imagine using many more opioids to override the blockade.”

This thought is a kind of hopeless, automatic one, such as “This won’t work for me,” or “I will just use on it.” We can remind our patient that a thought is simply a thought. Mindfulness can be used to help this patient identify and label his/her thoughts. The task is then to figure out whether it is wise to act on those thoughts. It is crucial to be able to monitor and track this kind of thinking to help a patient identify and manage cravings. These thoughts will happen, but the behavior does not have to follow. In dialectical behavior therapy, we help patients identify thoughts that come mostly from emotions, which are, for the most part, about having short-term relief rather than thoughts that are more balanced by emotion and reason. We call the latter kinds of thoughts “wise mind”; they are more focused on long-term goals. Clinicians should help the patient discern the difference between these different types of thoughts. Remember, if the patients are sitting in your office, there must have been some “wise mind thinking” that led them there, and you should highlight and explore why they made that choice in the first place.
 

Patient: “I want to have the ability to use opioids if things get really bad.”

Opioids can become a source of security and a reliable resource that doesn’t fail the patient when he or she is struggling. Most of the time, patients have gotten to a place in which opioids are the only coping skill they have to manage life’s difficulties. These clients need to relearn alternative coping skills. Using Vivitrol gives them the ability to be sober enough to practice distress tolerance skills and realize the benefits of not using opioids. Learning how to distract, soothe, and use relaxation strategies are the only ways they are going to be able to build a satisfying life again without substance use. If we can hold up the dilemma facing this person by saying “On the one hand, you are scared not to have your usual go-to; and on the other hand, you want things to change.” It may be helpful to have an in-depth discussion of what patients imagine might happen if they don’t have opioids to fall back on. This discussion may uncover the patients’ lack of confidence about being able to cope and a way to introduce some of the alternative coping strategies. It also may leave them with some concrete ways to manage the difficult feelings they are experiencing.
 

Patient: “What if I get in an accident and really need opioids?”

Some patients who have developed a dependence on opioids did so as a result of a past prescription for pain medication. They know very well the relationship between opioids and pain relief and the concern that they won’t have this option may be a real obstacle for them. Clinicians are in a position here to explain that, in most cases, patients can be treated with alternatives to opiate medication such as regional analgesia, nonopioid analgesics, and general anesthesia. In an emergency situation, a trained anesthesia provider is able to reverse the Vivitrol blockade so that the client can receive adequate pain management.
 

Patient: “I’m worried about side effects … ”

The most common side effects of Vivitrol are headache, nausea, somnolence, and vomiting. A serious but very rare complication is hepatocellular injury, but this is really only seen at extremely high doses of naltrexone (five times the approved dosage). If the patient is pregnant or planning pregnancy, she should consider alternative relapse-prevention medications, such as buprenorphine or methadone. If the patient has a proven allergy to naltrexone, polylactide-co-glycolide, carboxymethylcellulose, or any other component of the injection, Vivitrol should be avoided. As for the injection site, the client may experience some pain, tenderness, swelling, bruising. In very few cases, the site reaction can be severe. Again, here is an opportunity for a valuation of pros and cons of both continued opioid use and a Vivitrol trial.
 

Dr. Ascher is a board-certified general and addiction psychiatrist who serves as a clinical assistant professor in psychiatry at the University of Pennsylvania, Philadelphia, and is in private practice. Dr. Rosof is a clinical psychologist in Philadelphia with a specialty in addiction and extensive training in motivational approaches. Dr. Schack is a clinical psychologist who serves as an expert consultant with the Center for Motivation and Change and is private practice in Philadelphia and New York City. None of them have conflicts of interest to disclose.

As our nation faces an unprecedented opioid epidemic, mental health clinicians must communicate to patients options for treatment for opioid use disorders (OUDs). A small subset of patients who suffer from an OUD will be consistently motivated in their willingness to accept and fully engage in medically assisted treatment (MAT). However, most patients will display fluctuating degrees of intrinsic motivation in their perceived abilities, needs, and desires for MAT. As of 2017, the MAT agents that are approved for use in OUD by the Food and Drug Administration are methadone, buprenorphine, and naltrexone.

An obvious first step in treating these patients is to forge a therapeutic alliance that allows the patient to feel comfortable expressing myriad emotions, including shame, sadness, fear, anger, guilt, relief, hopefulness, and hopelessness. It is important for the clinician to have a nonjudgmental, kind, open, and empathic approach. We also must be able to specifically empathize with the ambivalence many patients feel regarding MAT. This column will review common questions and concerns that patients voice when contemplating the use of the long-acting injectable naltrexone (Vivitrol). In addition, this article will attempt to provide clinicians with possible responses to these questions, and aim to increase the likelihood that patients will be willing to accept treatment with Vivitrol.

Patient: “If I’m sober, then I should be completely sober, and that includes abstaining from Vivitrol.”

Here, this patient has expressed his/her point of view on what it means to be sober. This view is not uncommon. The clinician should explore the origin of this belief. This particular response may be internalized from an experience in a 12-step program. Or it may be a personal feeling. Engage in a conversation about what sobriety means to the patient, his or her personal goals, and thoughts related to how opiates might interfere with these goals. Clinicians should resist the urge to persuade a patient to use Vivitrol, regardless of how strongly the clinician feels about its effectiveness, in order to address the patient’s ambivalence. Join in with the patient to acknowledge and shed light on his or her perspective and ultimately support a well-informed decision that incorporates a patient’s individual values.
 

Patient: “Others will judge me and say that I can’t handle life without Vivitrol and I need a crutch.”

The truth is, others may think this. Clinicians should acknowledge that the influential people in the lives of our patients may very well be judgmental. But it is a potential barrier for this patient to be too concerned with others’ reaction to Vivitrol. Stay with the patient’s concern about being judged in order to move into a discussion about ways to tolerate that response. Maybe this is a time to ask whether it would be helpful to educate family members about Vivitrol or to problem-solve ways to handle interactions with others when they say this. It also might be a time to explore questions such as “Why is needing a crutch a sign of weakness to you?” Take a moment to understand the patient’s feelings about using “crutches.” This may open up the dialogue and the potential for seeing Vivitrol as a helpful resource rather than a sign of weakness.

Patient: “If I am doing so well, why introduce another medication?”

That is a valid question, especially if the patient has experienced real change and doesn’t see a need to mix things up. You can tell them that they may be right. However, this also is an opportunity to engage in a meaningful discussion with the patient about the nature of addiction and the nature of motivation. It may be helpful to review the triggers and patterns of use for this particular patient. Remind him or her that motivation to stay sober is fluid. People in the process of change typically are in regular dialogue with themselves about what they want, why they want it, and what they need to do. It is a natural part of the process to sometimes favor sobriety, while other times want to use. Vivitrol is ONE way to manage the relationship between these fluctuations and the desire to act on urges. This may be an appropriate time to tell the patient about other patients’ experiences with Vivitrol and how they experienced relief from not having to work through the costs and benefits of using on a constant basis.
 

Patient: “I feel controlled by Vivitrol, and it brings up a lot of emotions for me.”

For the most part, Vivitrol will remove the person’s day-to-day participation in their decision to use drugs. This is unsettling for many of our patients who find that using a substance of their own volition makes them feel more in control than does taking a prescribed medicine. The decision to use Vivitrol to treat their addiction is asking patients to think ahead and face what comes up day to day in ways they may not have. Clients can experience fear and sadness when attempting to manage life without the “escape hatch.” It’s natural to want to fight against any feelings of being controlled. To work through ambivalence, allow the patient to air these concerns, acknowledge that feeling controlled understandably is an uncomfortable experience, and then move into ways the patient may see Vivitrol as giving them more control. It is in this kind of conversation about the pros and cons that we can help a patient recognize what feels “wise” in the long term.

Patient: “If I take Vivitrol, I could imagine using many more opioids to override the blockade.”

This thought is a kind of hopeless, automatic one, such as “This won’t work for me,” or “I will just use on it.” We can remind our patient that a thought is simply a thought. Mindfulness can be used to help this patient identify and label his/her thoughts. The task is then to figure out whether it is wise to act on those thoughts. It is crucial to be able to monitor and track this kind of thinking to help a patient identify and manage cravings. These thoughts will happen, but the behavior does not have to follow. In dialectical behavior therapy, we help patients identify thoughts that come mostly from emotions, which are, for the most part, about having short-term relief rather than thoughts that are more balanced by emotion and reason. We call the latter kinds of thoughts “wise mind”; they are more focused on long-term goals. Clinicians should help the patient discern the difference between these different types of thoughts. Remember, if the patients are sitting in your office, there must have been some “wise mind thinking” that led them there, and you should highlight and explore why they made that choice in the first place.
 

Patient: “I want to have the ability to use opioids if things get really bad.”

Opioids can become a source of security and a reliable resource that doesn’t fail the patient when he or she is struggling. Most of the time, patients have gotten to a place in which opioids are the only coping skill they have to manage life’s difficulties. These clients need to relearn alternative coping skills. Using Vivitrol gives them the ability to be sober enough to practice distress tolerance skills and realize the benefits of not using opioids. Learning how to distract, soothe, and use relaxation strategies are the only ways they are going to be able to build a satisfying life again without substance use. If we can hold up the dilemma facing this person by saying “On the one hand, you are scared not to have your usual go-to; and on the other hand, you want things to change.” It may be helpful to have an in-depth discussion of what patients imagine might happen if they don’t have opioids to fall back on. This discussion may uncover the patients’ lack of confidence about being able to cope and a way to introduce some of the alternative coping strategies. It also may leave them with some concrete ways to manage the difficult feelings they are experiencing.
 

Patient: “What if I get in an accident and really need opioids?”

Some patients who have developed a dependence on opioids did so as a result of a past prescription for pain medication. They know very well the relationship between opioids and pain relief and the concern that they won’t have this option may be a real obstacle for them. Clinicians are in a position here to explain that, in most cases, patients can be treated with alternatives to opiate medication such as regional analgesia, nonopioid analgesics, and general anesthesia. In an emergency situation, a trained anesthesia provider is able to reverse the Vivitrol blockade so that the client can receive adequate pain management.
 

Patient: “I’m worried about side effects … ”

The most common side effects of Vivitrol are headache, nausea, somnolence, and vomiting. A serious but very rare complication is hepatocellular injury, but this is really only seen at extremely high doses of naltrexone (five times the approved dosage). If the patient is pregnant or planning pregnancy, she should consider alternative relapse-prevention medications, such as buprenorphine or methadone. If the patient has a proven allergy to naltrexone, polylactide-co-glycolide, carboxymethylcellulose, or any other component of the injection, Vivitrol should be avoided. As for the injection site, the client may experience some pain, tenderness, swelling, bruising. In very few cases, the site reaction can be severe. Again, here is an opportunity for a valuation of pros and cons of both continued opioid use and a Vivitrol trial.
 

Dr. Ascher is a board-certified general and addiction psychiatrist who serves as a clinical assistant professor in psychiatry at the University of Pennsylvania, Philadelphia, and is in private practice. Dr. Rosof is a clinical psychologist in Philadelphia with a specialty in addiction and extensive training in motivational approaches. Dr. Schack is a clinical psychologist who serves as an expert consultant with the Center for Motivation and Change and is private practice in Philadelphia and New York City. None of them have conflicts of interest to disclose.

ORLANDO – An inactivated varicella zoster virus vaccine currently in development for adult patients undergoing autologous hematopoietic stem cell transplantation is efficacious and well tolerated, according to findings from a randomized, placebo-controlled, phase III trial.

During the course of the 2 1/2-year pivotal multicenter trial, confirmed herpes zoster infections occurred in 42 of 560 patients who were randomized to receive inactivated varicella zoster virus vaccine (ZV_IN) consistency lot (overall incidence of 32.8 cases/1,000 patient-years), compared with 113 of 564 patients who received placebo (overall incidence of 91.8/1,000 patient-years). The estimated vaccine efficacy was 63.8% after adjusting for age and duration of antiviral prophylaxis, Drew J. Winston, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The vaccine also was effective for reducing moderate and severe herpes zoster pain (estimated vaccine efficacy, 69.5%), for preventing postherpetic neuralgia (estimated vaccine efficacy, 83.7%), and for prevention of herpes zoster–related complications (estimated vaccine efficacy, 73.5%), he noted.

Study subjects were adults aged 18 years or older who were undergoing autologous hematopoietic stem cell transplantation (auto-HCT) for a malignancy or other indication. The most common underlying diseases were lymphoma and multiple myeloma. All patients had a history of varicella infection or were seropositive for varicella zoster virus (VZV) antibody, and had no history of VZV vaccine or herpes zoster infection within the prior year.

They were randomized to receive a four-dose regimen of either ZV_IN consistency lot, ZV_IN high-antigen lot, or placebo. A group of 106 patients who received the ZV_IN high-antigen lot were included in the safety analysis only. The first ZV_IN dose was administered about a month before transplantation, and doses two through four were administered about 30, 60, and 90 days after transplantation. About 90% in each group received antiviral agents after transplantation, and the duration of the use of antivirals also was similar in the groups. All patients were followed for the duration of the study, and those who developed herpes zoster were followed for 6 months after onset.

Herpes zoster cases were confirmed by polymerase chain reaction or by blinded endpoint committee adjudication.

Serious adverse events and vaccine-related serious adverse events occurred in a similar proportion of patients in the treatment and placebo groups (32.9% and 32.7%, and 0.8% and 0.9%, respectively). Vaccine-related events were primarily injection-site reactions. Systemic adverse events that occurred up to 28 days after vaccination were mainly gastrointestinal side effects, such as diarrhea, nausea, and vomiting. Pyrexia, oral mucositis, thrombocytopenia, and febrile neutropenia also were reported.

The most common serious adverse events were infectious complications, such as febrile neutropenia and relapse of underlying disease.

The findings are notable, as patients undergoing auto-HCT have an increased risk of developing herpes zoster infection and its complications, including postherpetic neuralgia, secondary bacterial infections, and disseminated VZV infection, as well as an increased risk of hospitalization and mortality, Dr. Winston explained.

Herpes zoster infections are associated primarily with cell-mediated immunity, and in older studies done prior to the routine use of antiviral prophylaxis, the reported incidence in auto-HCT patients was between 16% and 25%. Because of this high risk, current guidelines call for antiviral prophylaxis during auto-HCT, but even in this current era of acyclovir or valacyclovir prophylaxis, infections occur at relatively high rates after auto-HCT, he noted.

“Now another approach to prevention of herpes zoster infection is vaccination,” he said.

The live attenuated vaccine currently on the market is generally contraindicated in immunocompromised patients – at least in early period after transplantation, but ZV_IN showed promise with respect to safety in earlier studies, which led to the current trial.

“This study demonstrated that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr. Winston said, noting that efficacy was observed both in those younger than age 50 years and in those aged 50 and older, and also in those who received prophylaxis for less than 3 months and for 3-6 months.

“Finally!” said one audience member, who noted during a discussion of the findings that there has long been a need for a vaccine to prevent herpes zoster in auto-HCT patients.

Dr. Winston reported receiving research funding from Oxford, and serving as a consultant to Merck and Chimerix.

[email protected]

ORLANDO – An inactivated varicella zoster virus vaccine currently in development for adult patients undergoing autologous hematopoietic stem cell transplantation is efficacious and well tolerated, according to findings from a randomized, placebo-controlled, phase III trial.

During the course of the 2 1/2-year pivotal multicenter trial, confirmed herpes zoster infections occurred in 42 of 560 patients who were randomized to receive inactivated varicella zoster virus vaccine (ZV_IN) consistency lot (overall incidence of 32.8 cases/1,000 patient-years), compared with 113 of 564 patients who received placebo (overall incidence of 91.8/1,000 patient-years). The estimated vaccine efficacy was 63.8% after adjusting for age and duration of antiviral prophylaxis, Drew J. Winston, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The vaccine also was effective for reducing moderate and severe herpes zoster pain (estimated vaccine efficacy, 69.5%), for preventing postherpetic neuralgia (estimated vaccine efficacy, 83.7%), and for prevention of herpes zoster–related complications (estimated vaccine efficacy, 73.5%), he noted.

Study subjects were adults aged 18 years or older who were undergoing autologous hematopoietic stem cell transplantation (auto-HCT) for a malignancy or other indication. The most common underlying diseases were lymphoma and multiple myeloma. All patients had a history of varicella infection or were seropositive for varicella zoster virus (VZV) antibody, and had no history of VZV vaccine or herpes zoster infection within the prior year.

They were randomized to receive a four-dose regimen of either ZV_IN consistency lot, ZV_IN high-antigen lot, or placebo. A group of 106 patients who received the ZV_IN high-antigen lot were included in the safety analysis only. The first ZV_IN dose was administered about a month before transplantation, and doses two through four were administered about 30, 60, and 90 days after transplantation. About 90% in each group received antiviral agents after transplantation, and the duration of the use of antivirals also was similar in the groups. All patients were followed for the duration of the study, and those who developed herpes zoster were followed for 6 months after onset.

Herpes zoster cases were confirmed by polymerase chain reaction or by blinded endpoint committee adjudication.

Serious adverse events and vaccine-related serious adverse events occurred in a similar proportion of patients in the treatment and placebo groups (32.9% and 32.7%, and 0.8% and 0.9%, respectively). Vaccine-related events were primarily injection-site reactions. Systemic adverse events that occurred up to 28 days after vaccination were mainly gastrointestinal side effects, such as diarrhea, nausea, and vomiting. Pyrexia, oral mucositis, thrombocytopenia, and febrile neutropenia also were reported.

The most common serious adverse events were infectious complications, such as febrile neutropenia and relapse of underlying disease.

The findings are notable, as patients undergoing auto-HCT have an increased risk of developing herpes zoster infection and its complications, including postherpetic neuralgia, secondary bacterial infections, and disseminated VZV infection, as well as an increased risk of hospitalization and mortality, Dr. Winston explained.

Herpes zoster infections are associated primarily with cell-mediated immunity, and in older studies done prior to the routine use of antiviral prophylaxis, the reported incidence in auto-HCT patients was between 16% and 25%. Because of this high risk, current guidelines call for antiviral prophylaxis during auto-HCT, but even in this current era of acyclovir or valacyclovir prophylaxis, infections occur at relatively high rates after auto-HCT, he noted.

“Now another approach to prevention of herpes zoster infection is vaccination,” he said.

The live attenuated vaccine currently on the market is generally contraindicated in immunocompromised patients – at least in early period after transplantation, but ZV_IN showed promise with respect to safety in earlier studies, which led to the current trial.

“This study demonstrated that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr. Winston said, noting that efficacy was observed both in those younger than age 50 years and in those aged 50 and older, and also in those who received prophylaxis for less than 3 months and for 3-6 months.

“Finally!” said one audience member, who noted during a discussion of the findings that there has long been a need for a vaccine to prevent herpes zoster in auto-HCT patients.

Dr. Winston reported receiving research funding from Oxford, and serving as a consultant to Merck and Chimerix.

[email protected]

ORLANDO – An inactivated varicella zoster virus vaccine currently in development for adult patients undergoing autologous hematopoietic stem cell transplantation is efficacious and well tolerated, according to findings from a randomized, placebo-controlled, phase III trial.

During the course of the 2 1/2-year pivotal multicenter trial, confirmed herpes zoster infections occurred in 42 of 560 patients who were randomized to receive inactivated varicella zoster virus vaccine (ZV_IN) consistency lot (overall incidence of 32.8 cases/1,000 patient-years), compared with 113 of 564 patients who received placebo (overall incidence of 91.8/1,000 patient-years). The estimated vaccine efficacy was 63.8% after adjusting for age and duration of antiviral prophylaxis, Drew J. Winston, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The vaccine also was effective for reducing moderate and severe herpes zoster pain (estimated vaccine efficacy, 69.5%), for preventing postherpetic neuralgia (estimated vaccine efficacy, 83.7%), and for prevention of herpes zoster–related complications (estimated vaccine efficacy, 73.5%), he noted.

Study subjects were adults aged 18 years or older who were undergoing autologous hematopoietic stem cell transplantation (auto-HCT) for a malignancy or other indication. The most common underlying diseases were lymphoma and multiple myeloma. All patients had a history of varicella infection or were seropositive for varicella zoster virus (VZV) antibody, and had no history of VZV vaccine or herpes zoster infection within the prior year.

They were randomized to receive a four-dose regimen of either ZV_IN consistency lot, ZV_IN high-antigen lot, or placebo. A group of 106 patients who received the ZV_IN high-antigen lot were included in the safety analysis only. The first ZV_IN dose was administered about a month before transplantation, and doses two through four were administered about 30, 60, and 90 days after transplantation. About 90% in each group received antiviral agents after transplantation, and the duration of the use of antivirals also was similar in the groups. All patients were followed for the duration of the study, and those who developed herpes zoster were followed for 6 months after onset.

Herpes zoster cases were confirmed by polymerase chain reaction or by blinded endpoint committee adjudication.

Serious adverse events and vaccine-related serious adverse events occurred in a similar proportion of patients in the treatment and placebo groups (32.9% and 32.7%, and 0.8% and 0.9%, respectively). Vaccine-related events were primarily injection-site reactions. Systemic adverse events that occurred up to 28 days after vaccination were mainly gastrointestinal side effects, such as diarrhea, nausea, and vomiting. Pyrexia, oral mucositis, thrombocytopenia, and febrile neutropenia also were reported.

The most common serious adverse events were infectious complications, such as febrile neutropenia and relapse of underlying disease.

The findings are notable, as patients undergoing auto-HCT have an increased risk of developing herpes zoster infection and its complications, including postherpetic neuralgia, secondary bacterial infections, and disseminated VZV infection, as well as an increased risk of hospitalization and mortality, Dr. Winston explained.

Herpes zoster infections are associated primarily with cell-mediated immunity, and in older studies done prior to the routine use of antiviral prophylaxis, the reported incidence in auto-HCT patients was between 16% and 25%. Because of this high risk, current guidelines call for antiviral prophylaxis during auto-HCT, but even in this current era of acyclovir or valacyclovir prophylaxis, infections occur at relatively high rates after auto-HCT, he noted.

“Now another approach to prevention of herpes zoster infection is vaccination,” he said.

The live attenuated vaccine currently on the market is generally contraindicated in immunocompromised patients – at least in early period after transplantation, but ZV_IN showed promise with respect to safety in earlier studies, which led to the current trial.

“This study demonstrated that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr. Winston said, noting that efficacy was observed both in those younger than age 50 years and in those aged 50 and older, and also in those who received prophylaxis for less than 3 months and for 3-6 months.

“Finally!” said one audience member, who noted during a discussion of the findings that there has long been a need for a vaccine to prevent herpes zoster in auto-HCT patients.

Dr. Winston reported receiving research funding from Oxford, and serving as a consultant to Merck and Chimerix.

[email protected]

New guidelines recommend proactively screening for the late-term effects of both myeloma itself and the multiple therapies many patients receive.

“We are entering a watershed period in which patients are expecting to live in excess of 5 to 10 years after a diagnosis of myeloma, and issues of survivorship are becoming increasingly important,” wrote John A. Snowden, MD, of Sheffield (England) Teaching Hospitals NHS Foundation Trust and his associates on behalf of the UK Myeloma Forum and the British Society for Haematology.

Late effects of myeloma and therapies “constitute a unique syndrome,” the guideline authors emphasized. “Survivorship in myeloma therefore requires specialized screening, coordinated management and multidisciplinary care” (Br J Haematol. 2017 Jan 20. doi: 10.1111/bjh.14514).

Hung Kuo Chun/Thinkstock

About half of myeloma patients have renal impairment and should undergo routine tests of serum calcium, parathyroid hormone, and vitamin D, the authors stated. Moderate to severe renal impairment, renal-related hyperparathyroidism, and nephrotic syndrome merit specialty referrals, they added. They also advised carefully managing diabetes and hypertension to delay end-stage kidney disease, modifying doses of lenalidomide and bisphosphonate doses in renally impaired patients, avoiding nephrotoxic drugs when possible, and considering erythropoiesis-stimulating agents and iron supplementation for anemia.

Endocrine disorders are also common in myeloma, and the authors recommended annual screening for hypothyroidism, hypogonadism in males, and menopausal symptoms in younger females, especially after HSCT. They emphasized annual measurements of weight, height, body mass index, waist circumference, strength and frailty, blood pressure, HbA_1c, and serum lipids, with referral to primary care when needed. For bone loss, they emphasized weight-bearing exercise, bisphosphonates, dietary changes, and calcium and vitamin D supplementation. They recommended specialist input on hormone therapy, if indicated.

Spinal cord or nerve-root compression often accompanies myeloma, and long-term survivors also may have peripheral neuropathy secondary to chemotherapy and other drug treatments, the guidelines noted. They recommended testing thyroid function and vitamin B₁₂ levels, reducing or eliminating neurotoxic agents, offering gabapentin or pregabalin for symptom control, and referring patients to pain specialists and neurologists for peripheral neuropathy beyond grade I. They also advised annual ophthalmic screening because even intermittent high-dose corticosteroid therapy can lead to cataracts.

Cardiopulmonary abnormalities affect about half of myeloma patients and deserve heightened attention, the authors stressed. They recommended routinely screening cardiovascular risk factors, testing natriuretic peptide annually, and performing electrocardiograms, echocardiography, and pulmonary function tests in at-risk patients. They also advised diet, weight control, smoking cessation, physical activity, and specialist referral for patients with established cardiovascular or pulmonary disease.

Bisphosphonates can cause osteonecrosis of the jaw, and chemotherapy and other therapies can cause oral dryness. The guidelines emphasized – in addition to monitoring for these adverse outcomes – the importance of oral hygiene, artificial saliva rinses, annual dental exams, and specialty evaluations for nonhealing lesions.

Novel myeloma therapies often cause diarrhea, but chronic diarrhea should be evaluated by a gastroenterologist to rule out malignancies, underlying bowel disease, AL amyloidosis, and bile acid malabsorption, the authors stressed. They also recommended annual assessments of liver function tests, drug and alcohol history, and vitamin D, B₁₂, folate, and ferritin levels. Nutritionists should provide input if patients are losing weight, they added.

Myeloma confers at least eight times the risk of myelodysplastic syndrome and acute myeloid leukemia, compared with the general population, the guidelines noted. Second primary malignancies can result from long-term exposure to lenalidomide and to such alkylating agents as melphalan. They advised considering myelodysplastic syndrome and acute myeloid leukemia in patients with persistent or worsening cytopenias, investigating symptoms that could indicate other malignancies, participating in cancer screening registries, and developing formal surveillance for second primary malignancies.

Additional recommendations included baseline geriatric assessment in elderly and frail patients; holistic assessments at the start of each line of treatment to pinpoint needs and concerns and to plan support services; and regular assessments of mood, anxiety, and cognitive status, with referrals for therapy, psychiatry, and support groups as needed. The authors also stressed the role of routine holistic needs-assessments to detect and track both pain and fatigue. Therapy should always include prehabilitation and rehabilitation, and clinicians should recommend ongoing regular physical activity and a healthy lifestyle, they emphasized.

To develop the guidelines, the experts searched Medline and the Cochrane databases for literature published between 2006 and March 31, 2016. They based key recommendations on evidence from randomized, controlled trials. When those data were not available, they resorted to other studies and to consensus expert opinion. The recommendations take cost-effectiveness into account, but are not based on formal health economic assessments, the experts noted.

Myeloma UK paid for an independent medical writer to help search the literature and draft the manuscript. Dr. Snowden also disclosed support from Sheffield Hospitals Charity.

New guidelines recommend proactively screening for the late-term effects of both myeloma itself and the multiple therapies many patients receive.

“We are entering a watershed period in which patients are expecting to live in excess of 5 to 10 years after a diagnosis of myeloma, and issues of survivorship are becoming increasingly important,” wrote John A. Snowden, MD, of Sheffield (England) Teaching Hospitals NHS Foundation Trust and his associates on behalf of the UK Myeloma Forum and the British Society for Haematology.

Late effects of myeloma and therapies “constitute a unique syndrome,” the guideline authors emphasized. “Survivorship in myeloma therefore requires specialized screening, coordinated management and multidisciplinary care” (Br J Haematol. 2017 Jan 20. doi: 10.1111/bjh.14514).

Hung Kuo Chun/Thinkstock

About half of myeloma patients have renal impairment and should undergo routine tests of serum calcium, parathyroid hormone, and vitamin D, the authors stated. Moderate to severe renal impairment, renal-related hyperparathyroidism, and nephrotic syndrome merit specialty referrals, they added. They also advised carefully managing diabetes and hypertension to delay end-stage kidney disease, modifying doses of lenalidomide and bisphosphonate doses in renally impaired patients, avoiding nephrotoxic drugs when possible, and considering erythropoiesis-stimulating agents and iron supplementation for anemia.

Endocrine disorders are also common in myeloma, and the authors recommended annual screening for hypothyroidism, hypogonadism in males, and menopausal symptoms in younger females, especially after HSCT. They emphasized annual measurements of weight, height, body mass index, waist circumference, strength and frailty, blood pressure, HbA_1c, and serum lipids, with referral to primary care when needed. For bone loss, they emphasized weight-bearing exercise, bisphosphonates, dietary changes, and calcium and vitamin D supplementation. They recommended specialist input on hormone therapy, if indicated.

Spinal cord or nerve-root compression often accompanies myeloma, and long-term survivors also may have peripheral neuropathy secondary to chemotherapy and other drug treatments, the guidelines noted. They recommended testing thyroid function and vitamin B₁₂ levels, reducing or eliminating neurotoxic agents, offering gabapentin or pregabalin for symptom control, and referring patients to pain specialists and neurologists for peripheral neuropathy beyond grade I. They also advised annual ophthalmic screening because even intermittent high-dose corticosteroid therapy can lead to cataracts.

Cardiopulmonary abnormalities affect about half of myeloma patients and deserve heightened attention, the authors stressed. They recommended routinely screening cardiovascular risk factors, testing natriuretic peptide annually, and performing electrocardiograms, echocardiography, and pulmonary function tests in at-risk patients. They also advised diet, weight control, smoking cessation, physical activity, and specialist referral for patients with established cardiovascular or pulmonary disease.

Bisphosphonates can cause osteonecrosis of the jaw, and chemotherapy and other therapies can cause oral dryness. The guidelines emphasized – in addition to monitoring for these adverse outcomes – the importance of oral hygiene, artificial saliva rinses, annual dental exams, and specialty evaluations for nonhealing lesions.

Novel myeloma therapies often cause diarrhea, but chronic diarrhea should be evaluated by a gastroenterologist to rule out malignancies, underlying bowel disease, AL amyloidosis, and bile acid malabsorption, the authors stressed. They also recommended annual assessments of liver function tests, drug and alcohol history, and vitamin D, B₁₂, folate, and ferritin levels. Nutritionists should provide input if patients are losing weight, they added.

Myeloma confers at least eight times the risk of myelodysplastic syndrome and acute myeloid leukemia, compared with the general population, the guidelines noted. Second primary malignancies can result from long-term exposure to lenalidomide and to such alkylating agents as melphalan. They advised considering myelodysplastic syndrome and acute myeloid leukemia in patients with persistent or worsening cytopenias, investigating symptoms that could indicate other malignancies, participating in cancer screening registries, and developing formal surveillance for second primary malignancies.

Additional recommendations included baseline geriatric assessment in elderly and frail patients; holistic assessments at the start of each line of treatment to pinpoint needs and concerns and to plan support services; and regular assessments of mood, anxiety, and cognitive status, with referrals for therapy, psychiatry, and support groups as needed. The authors also stressed the role of routine holistic needs-assessments to detect and track both pain and fatigue. Therapy should always include prehabilitation and rehabilitation, and clinicians should recommend ongoing regular physical activity and a healthy lifestyle, they emphasized.

To develop the guidelines, the experts searched Medline and the Cochrane databases for literature published between 2006 and March 31, 2016. They based key recommendations on evidence from randomized, controlled trials. When those data were not available, they resorted to other studies and to consensus expert opinion. The recommendations take cost-effectiveness into account, but are not based on formal health economic assessments, the experts noted.

Myeloma UK paid for an independent medical writer to help search the literature and draft the manuscript. Dr. Snowden also disclosed support from Sheffield Hospitals Charity.

New guidelines recommend proactively screening for the late-term effects of both myeloma itself and the multiple therapies many patients receive.

“We are entering a watershed period in which patients are expecting to live in excess of 5 to 10 years after a diagnosis of myeloma, and issues of survivorship are becoming increasingly important,” wrote John A. Snowden, MD, of Sheffield (England) Teaching Hospitals NHS Foundation Trust and his associates on behalf of the UK Myeloma Forum and the British Society for Haematology.

Late effects of myeloma and therapies “constitute a unique syndrome,” the guideline authors emphasized. “Survivorship in myeloma therefore requires specialized screening, coordinated management and multidisciplinary care” (Br J Haematol. 2017 Jan 20. doi: 10.1111/bjh.14514).

Hung Kuo Chun/Thinkstock

About half of myeloma patients have renal impairment and should undergo routine tests of serum calcium, parathyroid hormone, and vitamin D, the authors stated. Moderate to severe renal impairment, renal-related hyperparathyroidism, and nephrotic syndrome merit specialty referrals, they added. They also advised carefully managing diabetes and hypertension to delay end-stage kidney disease, modifying doses of lenalidomide and bisphosphonate doses in renally impaired patients, avoiding nephrotoxic drugs when possible, and considering erythropoiesis-stimulating agents and iron supplementation for anemia.

Endocrine disorders are also common in myeloma, and the authors recommended annual screening for hypothyroidism, hypogonadism in males, and menopausal symptoms in younger females, especially after HSCT. They emphasized annual measurements of weight, height, body mass index, waist circumference, strength and frailty, blood pressure, HbA_1c, and serum lipids, with referral to primary care when needed. For bone loss, they emphasized weight-bearing exercise, bisphosphonates, dietary changes, and calcium and vitamin D supplementation. They recommended specialist input on hormone therapy, if indicated.

Spinal cord or nerve-root compression often accompanies myeloma, and long-term survivors also may have peripheral neuropathy secondary to chemotherapy and other drug treatments, the guidelines noted. They recommended testing thyroid function and vitamin B₁₂ levels, reducing or eliminating neurotoxic agents, offering gabapentin or pregabalin for symptom control, and referring patients to pain specialists and neurologists for peripheral neuropathy beyond grade I. They also advised annual ophthalmic screening because even intermittent high-dose corticosteroid therapy can lead to cataracts.

Cardiopulmonary abnormalities affect about half of myeloma patients and deserve heightened attention, the authors stressed. They recommended routinely screening cardiovascular risk factors, testing natriuretic peptide annually, and performing electrocardiograms, echocardiography, and pulmonary function tests in at-risk patients. They also advised diet, weight control, smoking cessation, physical activity, and specialist referral for patients with established cardiovascular or pulmonary disease.

Bisphosphonates can cause osteonecrosis of the jaw, and chemotherapy and other therapies can cause oral dryness. The guidelines emphasized – in addition to monitoring for these adverse outcomes – the importance of oral hygiene, artificial saliva rinses, annual dental exams, and specialty evaluations for nonhealing lesions.

Novel myeloma therapies often cause diarrhea, but chronic diarrhea should be evaluated by a gastroenterologist to rule out malignancies, underlying bowel disease, AL amyloidosis, and bile acid malabsorption, the authors stressed. They also recommended annual assessments of liver function tests, drug and alcohol history, and vitamin D, B₁₂, folate, and ferritin levels. Nutritionists should provide input if patients are losing weight, they added.

Myeloma confers at least eight times the risk of myelodysplastic syndrome and acute myeloid leukemia, compared with the general population, the guidelines noted. Second primary malignancies can result from long-term exposure to lenalidomide and to such alkylating agents as melphalan. They advised considering myelodysplastic syndrome and acute myeloid leukemia in patients with persistent or worsening cytopenias, investigating symptoms that could indicate other malignancies, participating in cancer screening registries, and developing formal surveillance for second primary malignancies.

Additional recommendations included baseline geriatric assessment in elderly and frail patients; holistic assessments at the start of each line of treatment to pinpoint needs and concerns and to plan support services; and regular assessments of mood, anxiety, and cognitive status, with referrals for therapy, psychiatry, and support groups as needed. The authors also stressed the role of routine holistic needs-assessments to detect and track both pain and fatigue. Therapy should always include prehabilitation and rehabilitation, and clinicians should recommend ongoing regular physical activity and a healthy lifestyle, they emphasized.

To develop the guidelines, the experts searched Medline and the Cochrane databases for literature published between 2006 and March 31, 2016. They based key recommendations on evidence from randomized, controlled trials. When those data were not available, they resorted to other studies and to consensus expert opinion. The recommendations take cost-effectiveness into account, but are not based on formal health economic assessments, the experts noted.

Myeloma UK paid for an independent medical writer to help search the literature and draft the manuscript. Dr. Snowden also disclosed support from Sheffield Hospitals Charity.

High baseline levels of circulating bacterial DNA increased the odds of serious infections by nearly fivefold in patients receiving prednisolone for severe alcoholic hepatitis, even after controlling for MELD score and white blood cell count, investigators reported in the April issue of Gastroenterology (2016 Dec 31. doi: 10.1053/j.gastro.2016.08.029).

“Patients with severe alcoholic hepatitis given prednisolone are at greater risk for developing serious infections and infections after treatment than patients not given prednisolone, which may offset its therapeutic benefit,” Nikhil Vergis, MD, and his associates wrote in Gastroenterology. “Level of circulating bacterial DNA before treatment could identify patients at high risk of infection if given prednisolone, which could be used to select therapies for patients with severe alcoholic hepatitis.”

Wavebreakmedia Ltd/ThinkStockPhotos.com

To further explore rates and predictors of infections in STOPAH, the researchers analyzed longitudinal data on incident infections for 1,092 trial participants who received either prednisolone (40 mg daily) or pentoxifylline (400 mg three times daily). For 731 patients, they also examined whether baseline circulating levels of 16s ribosomal bacterial DNA were associated with infections.

A total of 135 patients (12%) had an infection at baseline, 251 (23%) developed infections during treatment, and 89 (8%) developed infections after treatment, the investigators reported. Prednisolone therapy was not associated with infections during treatment, but was associated with a nearly 30% rise in the odds of serious posttreatment infections compared with pentoxifylline (odds ratio, 1.27; 95% confidence interval, 1.27-2.92; P = .002). Prednisolone recipients who developed infections were significantly more likely to die within 90 days than those who did not, even after controlling for end-stage liver disease or Lille score (OR, 2.5; 95% CI, 1.4-4.3; P = .002). Antibiotic therapy appeared to significantly reduce the risk of mortality among infected prednisolone recipients (13% vs. 52%; OR, 0.13; 95% CI 0.04-0.47; P = .002).

There was “a striking association between bacterial DNA and the development of infection within 7 days in patients treated with prednisolone,” the researchers reported. These patients had a median baseline circulating DNA level of 20.9 pg/mL, while prednisolone recipients who did not develop infections had a median baseline bacterial DNA level of 8.3 pg/mL (P = .004). Bacterial DNA predicted infections with an area under receiver operating characteristic curve of 0.70 (95% CI, 0.58-0.83; P = .003), which substantially exceeded the curve for white blood cell count (0.58).

A cut-off value of 18.5 pg/mL was 80% specific for predicting infection within 7 days of prednisolone therapy, the investigators also reported. Bacterial DNA level did not, however, predict infections within 7 days of pentoxifylline therapy, and pentoxifylline was not linked with infections that were serious, infections during treatment, or infections after treatment. (P =.08).

Using bacterial DNA levels to guide prednisolone prescription also appeared to reduce 90-day mortality in this patient population, although the effect achieved borderline statistical significance, the researchers said. “Larger prospective randomized studies are needed to definitely report whether bacterial DNA-guided therapy can [have an] impact on mortality in severe alcoholic hepatitis, and perhaps in other acute inflammatory conditions” in which immunosuppression is required, they added.

The National Institute for Health Research and Wellcome Trust and Medical Research Council provided funding. Dr. Vergis and 10 coinvestigators disclosed no conflicts of interest. Senior author Dr. Mark Thursz and one coinvestigator disclosed ties to Gilead, Bristol-Myers Squibb, AbbVie, Abbott, and Norgine.

Source: American Gastroenterological Association

High baseline levels of circulating bacterial DNA increased the odds of serious infections by nearly fivefold in patients receiving prednisolone for severe alcoholic hepatitis, even after controlling for MELD score and white blood cell count, investigators reported in the April issue of Gastroenterology (2016 Dec 31. doi: 10.1053/j.gastro.2016.08.029).

“Patients with severe alcoholic hepatitis given prednisolone are at greater risk for developing serious infections and infections after treatment than patients not given prednisolone, which may offset its therapeutic benefit,” Nikhil Vergis, MD, and his associates wrote in Gastroenterology. “Level of circulating bacterial DNA before treatment could identify patients at high risk of infection if given prednisolone, which could be used to select therapies for patients with severe alcoholic hepatitis.”

Wavebreakmedia Ltd/ThinkStockPhotos.com

To further explore rates and predictors of infections in STOPAH, the researchers analyzed longitudinal data on incident infections for 1,092 trial participants who received either prednisolone (40 mg daily) or pentoxifylline (400 mg three times daily). For 731 patients, they also examined whether baseline circulating levels of 16s ribosomal bacterial DNA were associated with infections.

A total of 135 patients (12%) had an infection at baseline, 251 (23%) developed infections during treatment, and 89 (8%) developed infections after treatment, the investigators reported. Prednisolone therapy was not associated with infections during treatment, but was associated with a nearly 30% rise in the odds of serious posttreatment infections compared with pentoxifylline (odds ratio, 1.27; 95% confidence interval, 1.27-2.92; P = .002). Prednisolone recipients who developed infections were significantly more likely to die within 90 days than those who did not, even after controlling for end-stage liver disease or Lille score (OR, 2.5; 95% CI, 1.4-4.3; P = .002). Antibiotic therapy appeared to significantly reduce the risk of mortality among infected prednisolone recipients (13% vs. 52%; OR, 0.13; 95% CI 0.04-0.47; P = .002).

There was “a striking association between bacterial DNA and the development of infection within 7 days in patients treated with prednisolone,” the researchers reported. These patients had a median baseline circulating DNA level of 20.9 pg/mL, while prednisolone recipients who did not develop infections had a median baseline bacterial DNA level of 8.3 pg/mL (P = .004). Bacterial DNA predicted infections with an area under receiver operating characteristic curve of 0.70 (95% CI, 0.58-0.83; P = .003), which substantially exceeded the curve for white blood cell count (0.58).

A cut-off value of 18.5 pg/mL was 80% specific for predicting infection within 7 days of prednisolone therapy, the investigators also reported. Bacterial DNA level did not, however, predict infections within 7 days of pentoxifylline therapy, and pentoxifylline was not linked with infections that were serious, infections during treatment, or infections after treatment. (P =.08).

Using bacterial DNA levels to guide prednisolone prescription also appeared to reduce 90-day mortality in this patient population, although the effect achieved borderline statistical significance, the researchers said. “Larger prospective randomized studies are needed to definitely report whether bacterial DNA-guided therapy can [have an] impact on mortality in severe alcoholic hepatitis, and perhaps in other acute inflammatory conditions” in which immunosuppression is required, they added.

The National Institute for Health Research and Wellcome Trust and Medical Research Council provided funding. Dr. Vergis and 10 coinvestigators disclosed no conflicts of interest. Senior author Dr. Mark Thursz and one coinvestigator disclosed ties to Gilead, Bristol-Myers Squibb, AbbVie, Abbott, and Norgine.

Source: American Gastroenterological Association

High baseline levels of circulating bacterial DNA increased the odds of serious infections by nearly fivefold in patients receiving prednisolone for severe alcoholic hepatitis, even after controlling for MELD score and white blood cell count, investigators reported in the April issue of Gastroenterology (2016 Dec 31. doi: 10.1053/j.gastro.2016.08.029).

“Patients with severe alcoholic hepatitis given prednisolone are at greater risk for developing serious infections and infections after treatment than patients not given prednisolone, which may offset its therapeutic benefit,” Nikhil Vergis, MD, and his associates wrote in Gastroenterology. “Level of circulating bacterial DNA before treatment could identify patients at high risk of infection if given prednisolone, which could be used to select therapies for patients with severe alcoholic hepatitis.”

Wavebreakmedia Ltd/ThinkStockPhotos.com

To further explore rates and predictors of infections in STOPAH, the researchers analyzed longitudinal data on incident infections for 1,092 trial participants who received either prednisolone (40 mg daily) or pentoxifylline (400 mg three times daily). For 731 patients, they also examined whether baseline circulating levels of 16s ribosomal bacterial DNA were associated with infections.

A total of 135 patients (12%) had an infection at baseline, 251 (23%) developed infections during treatment, and 89 (8%) developed infections after treatment, the investigators reported. Prednisolone therapy was not associated with infections during treatment, but was associated with a nearly 30% rise in the odds of serious posttreatment infections compared with pentoxifylline (odds ratio, 1.27; 95% confidence interval, 1.27-2.92; P = .002). Prednisolone recipients who developed infections were significantly more likely to die within 90 days than those who did not, even after controlling for end-stage liver disease or Lille score (OR, 2.5; 95% CI, 1.4-4.3; P = .002). Antibiotic therapy appeared to significantly reduce the risk of mortality among infected prednisolone recipients (13% vs. 52%; OR, 0.13; 95% CI 0.04-0.47; P = .002).

There was “a striking association between bacterial DNA and the development of infection within 7 days in patients treated with prednisolone,” the researchers reported. These patients had a median baseline circulating DNA level of 20.9 pg/mL, while prednisolone recipients who did not develop infections had a median baseline bacterial DNA level of 8.3 pg/mL (P = .004). Bacterial DNA predicted infections with an area under receiver operating characteristic curve of 0.70 (95% CI, 0.58-0.83; P = .003), which substantially exceeded the curve for white blood cell count (0.58).

A cut-off value of 18.5 pg/mL was 80% specific for predicting infection within 7 days of prednisolone therapy, the investigators also reported. Bacterial DNA level did not, however, predict infections within 7 days of pentoxifylline therapy, and pentoxifylline was not linked with infections that were serious, infections during treatment, or infections after treatment. (P =.08).

Using bacterial DNA levels to guide prednisolone prescription also appeared to reduce 90-day mortality in this patient population, although the effect achieved borderline statistical significance, the researchers said. “Larger prospective randomized studies are needed to definitely report whether bacterial DNA-guided therapy can [have an] impact on mortality in severe alcoholic hepatitis, and perhaps in other acute inflammatory conditions” in which immunosuppression is required, they added.

The National Institute for Health Research and Wellcome Trust and Medical Research Council provided funding. Dr. Vergis and 10 coinvestigators disclosed no conflicts of interest. Senior author Dr. Mark Thursz and one coinvestigator disclosed ties to Gilead, Bristol-Myers Squibb, AbbVie, Abbott, and Norgine.

Source: American Gastroenterological Association

Daratumumab (Darzalex) Photo courtesy of Janssen

The CHMP recommended approving daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone as treatment for adults with multiple myeloma (MM) who have received at least 1 prior therapy.

The CHMP’s recommendation has been forwarded to the European Commission, which is expected to make its decision on daratumumab within 2 months.

Daratumumab is a human IgG1k monoclonal antibody that binds to CD38, which is highly expressed on the surface of MM cells.

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license from Genmab.

Phase 3 trials

The CHMP’s recommendation regarding daratumumab was based on data from the phase 3 POLLUX and CASTOR trials.

In the POLLUX trial, researchers compared treatment with lenalidomide and dexamethasone to treatment with daratumumab, lenalidomide, and dexamethasone in patients with relapsed or refractory MM.

Patients who received daratumumab in combination had a significantly higher response rate and longer progression-free survival than patients who received the 2-drug combination.

However, treatment with daratumumab was associated with infusion-related reactions and a higher incidence of neutropenia.

Results from this trial were published in NEJM in October 2016.

In the CASTOR trial, researchers compared treatment with bortezomib and dexamethasone to treatment with daratumumab, bortezomib, and dexamethasone in patients with previously treated MM.

Patients who received the 3-drug combination had a higher response rate, longer progression-free survival, and a higher incidence of grade 3/4 adverse events than those who received the 2-drug combination.

Results from this trial were published in NEJM in August 2016.

Daratumumab (Darzalex) Photo courtesy of Janssen

The CHMP recommended approving daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone as treatment for adults with multiple myeloma (MM) who have received at least 1 prior therapy.

The CHMP’s recommendation has been forwarded to the European Commission, which is expected to make its decision on daratumumab within 2 months.

Daratumumab is a human IgG1k monoclonal antibody that binds to CD38, which is highly expressed on the surface of MM cells.

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license from Genmab.

Phase 3 trials

The CHMP’s recommendation regarding daratumumab was based on data from the phase 3 POLLUX and CASTOR trials.

In the POLLUX trial, researchers compared treatment with lenalidomide and dexamethasone to treatment with daratumumab, lenalidomide, and dexamethasone in patients with relapsed or refractory MM.

Patients who received daratumumab in combination had a significantly higher response rate and longer progression-free survival than patients who received the 2-drug combination.

However, treatment with daratumumab was associated with infusion-related reactions and a higher incidence of neutropenia.

Results from this trial were published in NEJM in October 2016.

In the CASTOR trial, researchers compared treatment with bortezomib and dexamethasone to treatment with daratumumab, bortezomib, and dexamethasone in patients with previously treated MM.

Patients who received the 3-drug combination had a higher response rate, longer progression-free survival, and a higher incidence of grade 3/4 adverse events than those who received the 2-drug combination.

Results from this trial were published in NEJM in August 2016.

Daratumumab (Darzalex) Photo courtesy of Janssen

The CHMP recommended approving daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone as treatment for adults with multiple myeloma (MM) who have received at least 1 prior therapy.

The CHMP’s recommendation has been forwarded to the European Commission, which is expected to make its decision on daratumumab within 2 months.

Daratumumab is a human IgG1k monoclonal antibody that binds to CD38, which is highly expressed on the surface of MM cells.

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license from Genmab.

Phase 3 trials

The CHMP’s recommendation regarding daratumumab was based on data from the phase 3 POLLUX and CASTOR trials.

In the POLLUX trial, researchers compared treatment with lenalidomide and dexamethasone to treatment with daratumumab, lenalidomide, and dexamethasone in patients with relapsed or refractory MM.

Patients who received daratumumab in combination had a significantly higher response rate and longer progression-free survival than patients who received the 2-drug combination.

However, treatment with daratumumab was associated with infusion-related reactions and a higher incidence of neutropenia.

Results from this trial were published in NEJM in October 2016.

In the CASTOR trial, researchers compared treatment with bortezomib and dexamethasone to treatment with daratumumab, bortezomib, and dexamethasone in patients with previously treated MM.

Patients who received the 3-drug combination had a higher response rate, longer progression-free survival, and a higher incidence of grade 3/4 adverse events than those who received the 2-drug combination.

Results from this trial were published in NEJM in August 2016.

The Food and Drug Administration has cleared the expanded use of a procalcitonin test to help determine antibiotic use in patients with lower respiratory tract infections (LRTI) and sepsis.

The Vidas Brahms PCT Assay (bioMérieux) uses procalcitonin levels to determine whether a patient with a lower respiratory tract infection (LRTI) should begin or remain on antibiotics and when antibiotics should be withdrawn in a patient with sepsis.

The test will be used primarily in hospital settings and emergency departments, according to the FDA. Test levels that are high levels suggest bacterial infection and the need for antibiotics while low levels indicate viral or noninfectious processes. However, concerns exist regarding false-positive or false-negative test results, which can prompt clinicians to prematurely stop or unnecessarily continue an antibiotic regimen in certain patients.

“Health care providers should not rely solely on PCT test results when making treatment decisions but should interpret test results in the context of a patient’s clinical status and other laboratory results,” according to the FDA statement.

The expanded use of the test was approved based on promising data from clinical trials that was presented at an FDA advisory committee meeting in November 2016. The Vidas Brahms test was already approved by the FDA for use in determining a patient’s risk of dying from sepsis. The test was cleared via the FDA 510(k) regulatory pathway, which is meant for tests or devices for which there is already something similar on the market.

Support for the test’s expanded usage comes from published prospective, randomized clinical trials that compared PCT-guided therapy with standard therapy. In those studies, patients who had received PCT-guided therapy experienced significant decreases in antibiotic use without significant affects to their safety.
 

[email protected]

The Food and Drug Administration has cleared the expanded use of a procalcitonin test to help determine antibiotic use in patients with lower respiratory tract infections (LRTI) and sepsis.

The Vidas Brahms PCT Assay (bioMérieux) uses procalcitonin levels to determine whether a patient with a lower respiratory tract infection (LRTI) should begin or remain on antibiotics and when antibiotics should be withdrawn in a patient with sepsis.

The test will be used primarily in hospital settings and emergency departments, according to the FDA. Test levels that are high levels suggest bacterial infection and the need for antibiotics while low levels indicate viral or noninfectious processes. However, concerns exist regarding false-positive or false-negative test results, which can prompt clinicians to prematurely stop or unnecessarily continue an antibiotic regimen in certain patients.

“Health care providers should not rely solely on PCT test results when making treatment decisions but should interpret test results in the context of a patient’s clinical status and other laboratory results,” according to the FDA statement.

The expanded use of the test was approved based on promising data from clinical trials that was presented at an FDA advisory committee meeting in November 2016. The Vidas Brahms test was already approved by the FDA for use in determining a patient’s risk of dying from sepsis. The test was cleared via the FDA 510(k) regulatory pathway, which is meant for tests or devices for which there is already something similar on the market.

Support for the test’s expanded usage comes from published prospective, randomized clinical trials that compared PCT-guided therapy with standard therapy. In those studies, patients who had received PCT-guided therapy experienced significant decreases in antibiotic use without significant affects to their safety.
 

[email protected]

The Food and Drug Administration has cleared the expanded use of a procalcitonin test to help determine antibiotic use in patients with lower respiratory tract infections (LRTI) and sepsis.

The Vidas Brahms PCT Assay (bioMérieux) uses procalcitonin levels to determine whether a patient with a lower respiratory tract infection (LRTI) should begin or remain on antibiotics and when antibiotics should be withdrawn in a patient with sepsis.

The test will be used primarily in hospital settings and emergency departments, according to the FDA. Test levels that are high levels suggest bacterial infection and the need for antibiotics while low levels indicate viral or noninfectious processes. However, concerns exist regarding false-positive or false-negative test results, which can prompt clinicians to prematurely stop or unnecessarily continue an antibiotic regimen in certain patients.

“Health care providers should not rely solely on PCT test results when making treatment decisions but should interpret test results in the context of a patient’s clinical status and other laboratory results,” according to the FDA statement.

The expanded use of the test was approved based on promising data from clinical trials that was presented at an FDA advisory committee meeting in November 2016. The Vidas Brahms test was already approved by the FDA for use in determining a patient’s risk of dying from sepsis. The test was cleared via the FDA 510(k) regulatory pathway, which is meant for tests or devices for which there is already something similar on the market.

Support for the test’s expanded usage comes from published prospective, randomized clinical trials that compared PCT-guided therapy with standard therapy. In those studies, patients who had received PCT-guided therapy experienced significant decreases in antibiotic use without significant affects to their safety.
 

[email protected]

Infections, autoimmune disease, bone marrow failure, medications, and total-body irradiation may induce CD4 lymphopenia, defined as a CD4 T-cell count below 300 cells/mL or less than 20% of total lymphocytes.¹ Human immunodeficiency virus (HIV) is the most common cause of CD4 lymphopenia, with sepsis (bacterial and fungal) and postoperative states the most common causes in hospital settings.² No underlying factors are found in 0.02% of CD4 lymphopenia cases, which are considered to be idiopathic.^3,4 We report a patient with cutaneous T-cell lymphoma (CTCL) who developed profound CD4 lymphopenia in the setting of long-term bexarotene therapy.

Case Report

A 63-year-old man with hypertension presented to our dermatology clinic with pruritic scaly plaques on the scalp of 4 months’ duration that had progressed to full-body exfoliative erythroderma (Figure 1). He had diffuse palmoplantar keratoderma and lymphadenopathy. His only long-term medications were terazosin for benign prostatic hyperplasia and atenolol for hypertension; he reported no new medications. Laboratory evaluation revealed normal liver and kidney function. A complete blood cell count (CBC) revealed a white blood cell (WBC) count within reference range (8000/µL [reference range, 4500–11,000/µL]) but with increased eosinophils (12.9% [reference range, 2.7%]) and monocytes (11.8% [reference range, 4%]) and reduced lymphocytes (16.8% [reference range, 34%]). Flow cytometry showed a CD4:CD8 ratio of 1.18 to 1 (reference range, 0.8–4.2)(absolute CD4⁺ cells, 764/µL [reference range, 297–1551/µL]; absolute CD8⁺ cells, 654/µL [reference range, 100–1047/µL]). Skin biopsy revealed subacute spongiotic dermatitis with numerous eosinophils, exocytosis including folliculotropism, and rare atypical lymphocytes (Figure 2). Molecular studies showed T-cell receptor γ gene rearrangement. The patient did not have any other underlying conditions that would predispose him to lymphopenia. Based on these findings, a diagnosis of CTCL stage IIIA was made and agreed on by experts at the University of California, San Diego Dermatology Grand Rounds.

The patient was subsequently started on acitretin, topical corticosteroids, and hydroxyzine. However, the erythroderma progressed and he developed fever, chills, and malaise, and he was hospitalized 2 months later for intensive therapy and to rule out infection. He improved on daily wet wraps, topical steroids, oral antibiotics, and initiation of narrowband UVB therapy. He was discharged 1 week later. Acitretin was switched to bexarotene 3 months later due to peeling and cracking of the palmoplantar skin. The initial dose was 225 mg once daily, which was steadily increased over the next 4 months to a therapeutic dose of 600 mg once daily, which was much lower than the maximum dose of 400 mg/m² daily (calculated at 750 mg/d in our patient). The patient achieved clinical remission 1 year after initiation of bexarotene in conjunction with narrowband UVB therapy. Serum eosinophils also normalized. Because there were no intolerable side effects, this dose was continued for 2 more years before it was slowly tapered to 375 mg once daily over a 1-year period. The new dose was maintained thereafter. Secondary hypertriglyceridemia and hypothyroidism, known side effects of bexarotene, developed 1 and 5 months after initiating therapy, respectively, and were treated with levothyroxine and fenofibrate. Blood counts were checked every 3 months and remained within reference range. Within the first few months of therapy, lymphocytes did trend down to 16.8%, but segmented neutrophils were normal at 59.4%. For the next 5 years the total WBC count and differential remained within reference range. T-cell subsets and flow cytometry data were not measured. No new medications were started during this period, and none of his existing medications had lymphopenia as a known side effect.

Five years after the initial diagnosis, the patient was still on bexarotene and was suspected to have pneumonia that was treated by his primary care provider with cefuroxime and azithromycin for 2 weeks with no improvement. He was then admitted to the hospital with shortness of breath, productive cough, night sweats, and dyspnea of 1 month’s duration. There was no associated weight loss or fever. Notably, the skin was clear. He was further treated for community-acquired pneumonia, first with vancomycin and ceftazidime, then with ciprofloxacin and sulfamethoxazole-trimethoprim, with no improvement. A CBC with differential was obtained on the patient’s first admission and revealed a WBC count of 3600/µL with decreased lymphocytes (8.6%), no eosinophilia, and anemia (hemoglobin, 10.5 g/dL [reference range, 33–37 g/dL]). T-cell subset studies revealed a CD4:CD8 ratio of 0.06 to 1 (absolute CD4⁺ cells, 6/µL; absolute CD8⁺ cells, 107/µL). The patient also had an elevated lactate dehydrogenase level of 1015 U/L (reference range, 100–200 U/L) and a normal comprehensive metabolic panel. A comprehensive workup, including urine and blood cultures, serum Cryptococcus and coccidioidomycosis IgG/IgM, histoplasmosis urine antigen, legionella, HIV, purified protein derivative (tuberculin), and aspergillosis galactomannan antigen panel, was negative. Blood tests for HIV and human T-lymphotropic virus also were negative. Bronchoscopy with cytology and sputum cultures for fungi, acid-fast bacteria, and viruses identified Pneumocystis jiroveci in the bronchial wash. Pneumocystis pneumonia was treated with intravenous clindamycin, primaquine, and leucovorin. The patient’s WBC count continued to drop over the next 2 weeks to a nadir of 1.7% with few lymphocytes noted on the differential. At that point, the bexarotene was stopped and was considered causative in inducing CD4 lymphopenia, resulting in opportunistic infection. The patient steadily improved and was discharged on sulfamethoxazole-trimethoprim prophylaxis for pneumocystis after a 4-month hospitalization.

His CD4 count slowly improved over the next 18 months; however, his skin disease recurred and progressed to exfoliative erythroderma with marked scarring alopecia (Figure 3), facial swelling, extreme pruritus, and notable eosinophilia. Repeat computed tomography was negative for extracutaneous involvement. A repeat skin biopsy showed recurrent mycosis fungoides similar to the original biopsy (Figure 4). Topical steroids and narrowband UVB therapy were restarted. A bone marrow biopsy revealed no definitive lymphoma, but the peripheral blood showed occasional CD8⁺ “flower cells” and no CD4⁺ Sézary cells. Two repeat molecular studies failed to show the T-cell receptor gene rearrangement. Localized electron beam radiation therapy, lenalidomide, and clobetasol were tried without benefit. The patient was hospitalized 3 months later and was started on wet wraps as well as weekly infusions of the histone deacetylase inhibitor romidepsin (14 mg/m² over a 4-hour period) on days 1, 8, and 15 of a 28-day cycle with rapid improvement. He experienced transient slight neutropenia with the first several treatments that quickly resolved. His skin was clear while on a regimen of triamcinolone, wet wraps, and intravenous romidepsin. He demonstrated visible improvement after 3 weekly infusions of romedepsin (Figure 5). His skin disease cleared after 9 infusions of romidepsin, and he currently remains in remission; however, he developed presumed bronchopneumonia after approximately 3 to 4 infusions. He then presented with severe headaches after his ninth infusion and was found to have cryptococcal meningitis. Romedepsin was stopped and he was treated with systemic antifungal therapy. His CTCL never recurred despite not restarting romidepsin.

Comment

The retinoids are chemically related to vitamin A. They regulate epithelial cell growth and are beneficial in inflammatory skin disorders and in patients with increased cell turnover as well as in skin cancer and precancer prevention/treatment.⁵ The first- and second-generation retinoids, isotretinoin and acitretin, respectively, cause anemia or leukopenia in less than 10% of patients; adverse effects are noted more commonly in doses greater than 1 mg/kg daily.^6-8

Bexarotene is a third-generation retinoid drug that is more selective for retinoid X receptors. It was approved in 1991 for treatment of advanced CTCL (stages IIB–IVB) in adult patients who have failed at least 1 prior systemic therapy. Bexarotene is noted to promote cell cycle arrest and apoptosis in CTCL cell lines.⁹ However, one study suggested that for bexarotene, inhibition of proliferation is more important than causing apoptosis in CTCL cells, and this effect is achieved through triggering the p53/p73-dependent cell cycle inhibition pathway.¹⁰ Studies in patients with Sézary syndrome have shown that bexarotene changes the chemokine receptor expression in circulating malignant T cells, making them less likely to traffic to the skin (lower chemokine receptor type 4 expression),¹¹ which may explain why some CTCL cases have shown improvement of skin disease on bexarotene despite progression of extradermal disease.¹²

Common side effects of bexarotene include hyperlipidemia and central hypothyroidism.¹³ In addition, dose-related myelosuppression with isolated leukopenia, particularly neutropenia, also has been reported (18% of patients at a dosage of 300 mg/m²/d and 43% of patients with a dosage greater than 300 mg/m²/d). Leukopenia generally occurs within the first 4 to 8 weeks of treatment, is relatively mild (WBC, 1000–2999/µL), and generally is reversible.^13-15 One review of 66 mycosis fungoides patients treated with bexarotene described a patient who developed leukopenia 15 months after initiating bexarotene therapy.¹⁴ The manufacturer recommends that treatment with bexarotene be continued as long as the patient is receiving benefit from the treatment. One trial of 70 mycosis fungoides patient treated with bexarotene reported response rates of 48% on bexarotene monotherapy (n=54) and 69% on bexarotene plus an additional agent (n=16).¹⁵ The authors noted higher response rates in patients on 2 lipid-lowering agents. They concluded that bexarotene was a safe and effective agent for treatment of cutaneous T-cell lymphoma and recommended continued treatment with a lowered dose of bexarotene in those achieving complete responses for a period of 2 years. Although the recommended initial dose is 300 mg/m²/d, bexarotene can be increased to 400 mg/m²/d after 8 weeks if no response to treatment is appreciated.¹⁶ Our patient was on a maximum bexarotene dose of 600 mg once daily (280 mg/m²/d) for the first 2 years, and a maintenance dose of 300 mg once daily for the next 3 years. He was not on any medicines known to induce leukopenia and he was not given any known cytochrome P450 3A4 inhibitors that could increase the toxicity of bexarotene.

The patient’s CBC was checked routinely every 2 to 3 months after he was started on bexarotene. For 5 years, the CBC and differential remained within reference range; however, his CD4 counts were not followed during those 5 years. We attribute his CD4 lymphopenia and subsequent pneumocystis pneumonia to bexarotene. After our patient’s CD4 lymphopenia was discovered, he developed a precipitous drop in his WBC and lymphocyte counts while hospitalized that worsened over a 2-week period. At this point, the bexarotene was discontinued and his WBC count slowly recovered. We believe that one of the initial antibiotics prescribed by the patient’s primary care physician at initial onset of pneumonia symptoms as an outpatient could have acted synergistically with bexarotene to worsen lymphopenia. Specifically, ceftazidime, vancomycin, and ciprofloxacin have all been reported to cause leukopenia; however, it was neutropenia in these cases, not lymphopenia.^17,18 Notwithstanding, the opportunistic pneumonia and therefore CD4 lymphopenia was present prior to any antibiotic use.

The CD4 lymphopenia was unlikely due to underlying infection(s) because an extensive workup was negative, except for the pneumocystis, which likely resulted from the lymphopenia. The CD4 lymphopenia also could be idiopathic, as it has been reported in 3 patients with mycosis fungoides.¹⁹ All 3 patients were erythrodermic at presentation and were noted to have numerous CD4⁺ lymphocytes in the cutaneous lesions but few circulating CD4⁺ T lymphocytes in the blood. The authors attributed the CD4 lymphopenia to cutaneous sequestration of CD4⁺ T lymphocytes.¹⁹ These cases contrast with our patient who was in clinical remission at the time of CD4 lymphopenia, which improved and normalized following discontinuation of bexarotene.

Conclusion

This case emphasizes the importance of monitoring for leukopenia, specifically CD4 lymphopenia, in patients on long-term bexarotene therapy. Routine CBC as well as T-cell subset counts should be performed during treatment. Rotation off bexarotene after several years of therapy should be considered, even in patients with continuous benefit from this systemic therapy.

Infections, autoimmune disease, bone marrow failure, medications, and total-body irradiation may induce CD4 lymphopenia, defined as a CD4 T-cell count below 300 cells/mL or less than 20% of total lymphocytes.¹ Human immunodeficiency virus (HIV) is the most common cause of CD4 lymphopenia, with sepsis (bacterial and fungal) and postoperative states the most common causes in hospital settings.² No underlying factors are found in 0.02% of CD4 lymphopenia cases, which are considered to be idiopathic.^3,4 We report a patient with cutaneous T-cell lymphoma (CTCL) who developed profound CD4 lymphopenia in the setting of long-term bexarotene therapy.

Case Report

A 63-year-old man with hypertension presented to our dermatology clinic with pruritic scaly plaques on the scalp of 4 months’ duration that had progressed to full-body exfoliative erythroderma (Figure 1). He had diffuse palmoplantar keratoderma and lymphadenopathy. His only long-term medications were terazosin for benign prostatic hyperplasia and atenolol for hypertension; he reported no new medications. Laboratory evaluation revealed normal liver and kidney function. A complete blood cell count (CBC) revealed a white blood cell (WBC) count within reference range (8000/µL [reference range, 4500–11,000/µL]) but with increased eosinophils (12.9% [reference range, 2.7%]) and monocytes (11.8% [reference range, 4%]) and reduced lymphocytes (16.8% [reference range, 34%]). Flow cytometry showed a CD4:CD8 ratio of 1.18 to 1 (reference range, 0.8–4.2)(absolute CD4⁺ cells, 764/µL [reference range, 297–1551/µL]; absolute CD8⁺ cells, 654/µL [reference range, 100–1047/µL]). Skin biopsy revealed subacute spongiotic dermatitis with numerous eosinophils, exocytosis including folliculotropism, and rare atypical lymphocytes (Figure 2). Molecular studies showed T-cell receptor γ gene rearrangement. The patient did not have any other underlying conditions that would predispose him to lymphopenia. Based on these findings, a diagnosis of CTCL stage IIIA was made and agreed on by experts at the University of California, San Diego Dermatology Grand Rounds.

The patient was subsequently started on acitretin, topical corticosteroids, and hydroxyzine. However, the erythroderma progressed and he developed fever, chills, and malaise, and he was hospitalized 2 months later for intensive therapy and to rule out infection. He improved on daily wet wraps, topical steroids, oral antibiotics, and initiation of narrowband UVB therapy. He was discharged 1 week later. Acitretin was switched to bexarotene 3 months later due to peeling and cracking of the palmoplantar skin. The initial dose was 225 mg once daily, which was steadily increased over the next 4 months to a therapeutic dose of 600 mg once daily, which was much lower than the maximum dose of 400 mg/m² daily (calculated at 750 mg/d in our patient). The patient achieved clinical remission 1 year after initiation of bexarotene in conjunction with narrowband UVB therapy. Serum eosinophils also normalized. Because there were no intolerable side effects, this dose was continued for 2 more years before it was slowly tapered to 375 mg once daily over a 1-year period. The new dose was maintained thereafter. Secondary hypertriglyceridemia and hypothyroidism, known side effects of bexarotene, developed 1 and 5 months after initiating therapy, respectively, and were treated with levothyroxine and fenofibrate. Blood counts were checked every 3 months and remained within reference range. Within the first few months of therapy, lymphocytes did trend down to 16.8%, but segmented neutrophils were normal at 59.4%. For the next 5 years the total WBC count and differential remained within reference range. T-cell subsets and flow cytometry data were not measured. No new medications were started during this period, and none of his existing medications had lymphopenia as a known side effect.

Five years after the initial diagnosis, the patient was still on bexarotene and was suspected to have pneumonia that was treated by his primary care provider with cefuroxime and azithromycin for 2 weeks with no improvement. He was then admitted to the hospital with shortness of breath, productive cough, night sweats, and dyspnea of 1 month’s duration. There was no associated weight loss or fever. Notably, the skin was clear. He was further treated for community-acquired pneumonia, first with vancomycin and ceftazidime, then with ciprofloxacin and sulfamethoxazole-trimethoprim, with no improvement. A CBC with differential was obtained on the patient’s first admission and revealed a WBC count of 3600/µL with decreased lymphocytes (8.6%), no eosinophilia, and anemia (hemoglobin, 10.5 g/dL [reference range, 33–37 g/dL]). T-cell subset studies revealed a CD4:CD8 ratio of 0.06 to 1 (absolute CD4⁺ cells, 6/µL; absolute CD8⁺ cells, 107/µL). The patient also had an elevated lactate dehydrogenase level of 1015 U/L (reference range, 100–200 U/L) and a normal comprehensive metabolic panel. A comprehensive workup, including urine and blood cultures, serum Cryptococcus and coccidioidomycosis IgG/IgM, histoplasmosis urine antigen, legionella, HIV, purified protein derivative (tuberculin), and aspergillosis galactomannan antigen panel, was negative. Blood tests for HIV and human T-lymphotropic virus also were negative. Bronchoscopy with cytology and sputum cultures for fungi, acid-fast bacteria, and viruses identified Pneumocystis jiroveci in the bronchial wash. Pneumocystis pneumonia was treated with intravenous clindamycin, primaquine, and leucovorin. The patient’s WBC count continued to drop over the next 2 weeks to a nadir of 1.7% with few lymphocytes noted on the differential. At that point, the bexarotene was stopped and was considered causative in inducing CD4 lymphopenia, resulting in opportunistic infection. The patient steadily improved and was discharged on sulfamethoxazole-trimethoprim prophylaxis for pneumocystis after a 4-month hospitalization.

His CD4 count slowly improved over the next 18 months; however, his skin disease recurred and progressed to exfoliative erythroderma with marked scarring alopecia (Figure 3), facial swelling, extreme pruritus, and notable eosinophilia. Repeat computed tomography was negative for extracutaneous involvement. A repeat skin biopsy showed recurrent mycosis fungoides similar to the original biopsy (Figure 4). Topical steroids and narrowband UVB therapy were restarted. A bone marrow biopsy revealed no definitive lymphoma, but the peripheral blood showed occasional CD8⁺ “flower cells” and no CD4⁺ Sézary cells. Two repeat molecular studies failed to show the T-cell receptor gene rearrangement. Localized electron beam radiation therapy, lenalidomide, and clobetasol were tried without benefit. The patient was hospitalized 3 months later and was started on wet wraps as well as weekly infusions of the histone deacetylase inhibitor romidepsin (14 mg/m² over a 4-hour period) on days 1, 8, and 15 of a 28-day cycle with rapid improvement. He experienced transient slight neutropenia with the first several treatments that quickly resolved. His skin was clear while on a regimen of triamcinolone, wet wraps, and intravenous romidepsin. He demonstrated visible improvement after 3 weekly infusions of romedepsin (Figure 5). His skin disease cleared after 9 infusions of romidepsin, and he currently remains in remission; however, he developed presumed bronchopneumonia after approximately 3 to 4 infusions. He then presented with severe headaches after his ninth infusion and was found to have cryptococcal meningitis. Romedepsin was stopped and he was treated with systemic antifungal therapy. His CTCL never recurred despite not restarting romidepsin.

Comment

The retinoids are chemically related to vitamin A. They regulate epithelial cell growth and are beneficial in inflammatory skin disorders and in patients with increased cell turnover as well as in skin cancer and precancer prevention/treatment.⁵ The first- and second-generation retinoids, isotretinoin and acitretin, respectively, cause anemia or leukopenia in less than 10% of patients; adverse effects are noted more commonly in doses greater than 1 mg/kg daily.^6-8

Bexarotene is a third-generation retinoid drug that is more selective for retinoid X receptors. It was approved in 1991 for treatment of advanced CTCL (stages IIB–IVB) in adult patients who have failed at least 1 prior systemic therapy. Bexarotene is noted to promote cell cycle arrest and apoptosis in CTCL cell lines.⁹ However, one study suggested that for bexarotene, inhibition of proliferation is more important than causing apoptosis in CTCL cells, and this effect is achieved through triggering the p53/p73-dependent cell cycle inhibition pathway.¹⁰ Studies in patients with Sézary syndrome have shown that bexarotene changes the chemokine receptor expression in circulating malignant T cells, making them less likely to traffic to the skin (lower chemokine receptor type 4 expression),¹¹ which may explain why some CTCL cases have shown improvement of skin disease on bexarotene despite progression of extradermal disease.¹²

Common side effects of bexarotene include hyperlipidemia and central hypothyroidism.¹³ In addition, dose-related myelosuppression with isolated leukopenia, particularly neutropenia, also has been reported (18% of patients at a dosage of 300 mg/m²/d and 43% of patients with a dosage greater than 300 mg/m²/d). Leukopenia generally occurs within the first 4 to 8 weeks of treatment, is relatively mild (WBC, 1000–2999/µL), and generally is reversible.^13-15 One review of 66 mycosis fungoides patients treated with bexarotene described a patient who developed leukopenia 15 months after initiating bexarotene therapy.¹⁴ The manufacturer recommends that treatment with bexarotene be continued as long as the patient is receiving benefit from the treatment. One trial of 70 mycosis fungoides patient treated with bexarotene reported response rates of 48% on bexarotene monotherapy (n=54) and 69% on bexarotene plus an additional agent (n=16).¹⁵ The authors noted higher response rates in patients on 2 lipid-lowering agents. They concluded that bexarotene was a safe and effective agent for treatment of cutaneous T-cell lymphoma and recommended continued treatment with a lowered dose of bexarotene in those achieving complete responses for a period of 2 years. Although the recommended initial dose is 300 mg/m²/d, bexarotene can be increased to 400 mg/m²/d after 8 weeks if no response to treatment is appreciated.¹⁶ Our patient was on a maximum bexarotene dose of 600 mg once daily (280 mg/m²/d) for the first 2 years, and a maintenance dose of 300 mg once daily for the next 3 years. He was not on any medicines known to induce leukopenia and he was not given any known cytochrome P450 3A4 inhibitors that could increase the toxicity of bexarotene.

The patient’s CBC was checked routinely every 2 to 3 months after he was started on bexarotene. For 5 years, the CBC and differential remained within reference range; however, his CD4 counts were not followed during those 5 years. We attribute his CD4 lymphopenia and subsequent pneumocystis pneumonia to bexarotene. After our patient’s CD4 lymphopenia was discovered, he developed a precipitous drop in his WBC and lymphocyte counts while hospitalized that worsened over a 2-week period. At this point, the bexarotene was discontinued and his WBC count slowly recovered. We believe that one of the initial antibiotics prescribed by the patient’s primary care physician at initial onset of pneumonia symptoms as an outpatient could have acted synergistically with bexarotene to worsen lymphopenia. Specifically, ceftazidime, vancomycin, and ciprofloxacin have all been reported to cause leukopenia; however, it was neutropenia in these cases, not lymphopenia.^17,18 Notwithstanding, the opportunistic pneumonia and therefore CD4 lymphopenia was present prior to any antibiotic use.

The CD4 lymphopenia was unlikely due to underlying infection(s) because an extensive workup was negative, except for the pneumocystis, which likely resulted from the lymphopenia. The CD4 lymphopenia also could be idiopathic, as it has been reported in 3 patients with mycosis fungoides.¹⁹ All 3 patients were erythrodermic at presentation and were noted to have numerous CD4⁺ lymphocytes in the cutaneous lesions but few circulating CD4⁺ T lymphocytes in the blood. The authors attributed the CD4 lymphopenia to cutaneous sequestration of CD4⁺ T lymphocytes.¹⁹ These cases contrast with our patient who was in clinical remission at the time of CD4 lymphopenia, which improved and normalized following discontinuation of bexarotene.

Conclusion

This case emphasizes the importance of monitoring for leukopenia, specifically CD4 lymphopenia, in patients on long-term bexarotene therapy. Routine CBC as well as T-cell subset counts should be performed during treatment. Rotation off bexarotene after several years of therapy should be considered, even in patients with continuous benefit from this systemic therapy.

Infections, autoimmune disease, bone marrow failure, medications, and total-body irradiation may induce CD4 lymphopenia, defined as a CD4 T-cell count below 300 cells/mL or less than 20% of total lymphocytes.¹ Human immunodeficiency virus (HIV) is the most common cause of CD4 lymphopenia, with sepsis (bacterial and fungal) and postoperative states the most common causes in hospital settings.² No underlying factors are found in 0.02% of CD4 lymphopenia cases, which are considered to be idiopathic.^3,4 We report a patient with cutaneous T-cell lymphoma (CTCL) who developed profound CD4 lymphopenia in the setting of long-term bexarotene therapy.

Case Report

A 63-year-old man with hypertension presented to our dermatology clinic with pruritic scaly plaques on the scalp of 4 months’ duration that had progressed to full-body exfoliative erythroderma (Figure 1). He had diffuse palmoplantar keratoderma and lymphadenopathy. His only long-term medications were terazosin for benign prostatic hyperplasia and atenolol for hypertension; he reported no new medications. Laboratory evaluation revealed normal liver and kidney function. A complete blood cell count (CBC) revealed a white blood cell (WBC) count within reference range (8000/µL [reference range, 4500–11,000/µL]) but with increased eosinophils (12.9% [reference range, 2.7%]) and monocytes (11.8% [reference range, 4%]) and reduced lymphocytes (16.8% [reference range, 34%]). Flow cytometry showed a CD4:CD8 ratio of 1.18 to 1 (reference range, 0.8–4.2)(absolute CD4⁺ cells, 764/µL [reference range, 297–1551/µL]; absolute CD8⁺ cells, 654/µL [reference range, 100–1047/µL]). Skin biopsy revealed subacute spongiotic dermatitis with numerous eosinophils, exocytosis including folliculotropism, and rare atypical lymphocytes (Figure 2). Molecular studies showed T-cell receptor γ gene rearrangement. The patient did not have any other underlying conditions that would predispose him to lymphopenia. Based on these findings, a diagnosis of CTCL stage IIIA was made and agreed on by experts at the University of California, San Diego Dermatology Grand Rounds.

The patient was subsequently started on acitretin, topical corticosteroids, and hydroxyzine. However, the erythroderma progressed and he developed fever, chills, and malaise, and he was hospitalized 2 months later for intensive therapy and to rule out infection. He improved on daily wet wraps, topical steroids, oral antibiotics, and initiation of narrowband UVB therapy. He was discharged 1 week later. Acitretin was switched to bexarotene 3 months later due to peeling and cracking of the palmoplantar skin. The initial dose was 225 mg once daily, which was steadily increased over the next 4 months to a therapeutic dose of 600 mg once daily, which was much lower than the maximum dose of 400 mg/m² daily (calculated at 750 mg/d in our patient). The patient achieved clinical remission 1 year after initiation of bexarotene in conjunction with narrowband UVB therapy. Serum eosinophils also normalized. Because there were no intolerable side effects, this dose was continued for 2 more years before it was slowly tapered to 375 mg once daily over a 1-year period. The new dose was maintained thereafter. Secondary hypertriglyceridemia and hypothyroidism, known side effects of bexarotene, developed 1 and 5 months after initiating therapy, respectively, and were treated with levothyroxine and fenofibrate. Blood counts were checked every 3 months and remained within reference range. Within the first few months of therapy, lymphocytes did trend down to 16.8%, but segmented neutrophils were normal at 59.4%. For the next 5 years the total WBC count and differential remained within reference range. T-cell subsets and flow cytometry data were not measured. No new medications were started during this period, and none of his existing medications had lymphopenia as a known side effect.

Five years after the initial diagnosis, the patient was still on bexarotene and was suspected to have pneumonia that was treated by his primary care provider with cefuroxime and azithromycin for 2 weeks with no improvement. He was then admitted to the hospital with shortness of breath, productive cough, night sweats, and dyspnea of 1 month’s duration. There was no associated weight loss or fever. Notably, the skin was clear. He was further treated for community-acquired pneumonia, first with vancomycin and ceftazidime, then with ciprofloxacin and sulfamethoxazole-trimethoprim, with no improvement. A CBC with differential was obtained on the patient’s first admission and revealed a WBC count of 3600/µL with decreased lymphocytes (8.6%), no eosinophilia, and anemia (hemoglobin, 10.5 g/dL [reference range, 33–37 g/dL]). T-cell subset studies revealed a CD4:CD8 ratio of 0.06 to 1 (absolute CD4⁺ cells, 6/µL; absolute CD8⁺ cells, 107/µL). The patient also had an elevated lactate dehydrogenase level of 1015 U/L (reference range, 100–200 U/L) and a normal comprehensive metabolic panel. A comprehensive workup, including urine and blood cultures, serum Cryptococcus and coccidioidomycosis IgG/IgM, histoplasmosis urine antigen, legionella, HIV, purified protein derivative (tuberculin), and aspergillosis galactomannan antigen panel, was negative. Blood tests for HIV and human T-lymphotropic virus also were negative. Bronchoscopy with cytology and sputum cultures for fungi, acid-fast bacteria, and viruses identified Pneumocystis jiroveci in the bronchial wash. Pneumocystis pneumonia was treated with intravenous clindamycin, primaquine, and leucovorin. The patient’s WBC count continued to drop over the next 2 weeks to a nadir of 1.7% with few lymphocytes noted on the differential. At that point, the bexarotene was stopped and was considered causative in inducing CD4 lymphopenia, resulting in opportunistic infection. The patient steadily improved and was discharged on sulfamethoxazole-trimethoprim prophylaxis for pneumocystis after a 4-month hospitalization.

His CD4 count slowly improved over the next 18 months; however, his skin disease recurred and progressed to exfoliative erythroderma with marked scarring alopecia (Figure 3), facial swelling, extreme pruritus, and notable eosinophilia. Repeat computed tomography was negative for extracutaneous involvement. A repeat skin biopsy showed recurrent mycosis fungoides similar to the original biopsy (Figure 4). Topical steroids and narrowband UVB therapy were restarted. A bone marrow biopsy revealed no definitive lymphoma, but the peripheral blood showed occasional CD8⁺ “flower cells” and no CD4⁺ Sézary cells. Two repeat molecular studies failed to show the T-cell receptor gene rearrangement. Localized electron beam radiation therapy, lenalidomide, and clobetasol were tried without benefit. The patient was hospitalized 3 months later and was started on wet wraps as well as weekly infusions of the histone deacetylase inhibitor romidepsin (14 mg/m² over a 4-hour period) on days 1, 8, and 15 of a 28-day cycle with rapid improvement. He experienced transient slight neutropenia with the first several treatments that quickly resolved. His skin was clear while on a regimen of triamcinolone, wet wraps, and intravenous romidepsin. He demonstrated visible improvement after 3 weekly infusions of romedepsin (Figure 5). His skin disease cleared after 9 infusions of romidepsin, and he currently remains in remission; however, he developed presumed bronchopneumonia after approximately 3 to 4 infusions. He then presented with severe headaches after his ninth infusion and was found to have cryptococcal meningitis. Romedepsin was stopped and he was treated with systemic antifungal therapy. His CTCL never recurred despite not restarting romidepsin.

Comment

The retinoids are chemically related to vitamin A. They regulate epithelial cell growth and are beneficial in inflammatory skin disorders and in patients with increased cell turnover as well as in skin cancer and precancer prevention/treatment.⁵ The first- and second-generation retinoids, isotretinoin and acitretin, respectively, cause anemia or leukopenia in less than 10% of patients; adverse effects are noted more commonly in doses greater than 1 mg/kg daily.^6-8

Bexarotene is a third-generation retinoid drug that is more selective for retinoid X receptors. It was approved in 1991 for treatment of advanced CTCL (stages IIB–IVB) in adult patients who have failed at least 1 prior systemic therapy. Bexarotene is noted to promote cell cycle arrest and apoptosis in CTCL cell lines.⁹ However, one study suggested that for bexarotene, inhibition of proliferation is more important than causing apoptosis in CTCL cells, and this effect is achieved through triggering the p53/p73-dependent cell cycle inhibition pathway.¹⁰ Studies in patients with Sézary syndrome have shown that bexarotene changes the chemokine receptor expression in circulating malignant T cells, making them less likely to traffic to the skin (lower chemokine receptor type 4 expression),¹¹ which may explain why some CTCL cases have shown improvement of skin disease on bexarotene despite progression of extradermal disease.¹²

Common side effects of bexarotene include hyperlipidemia and central hypothyroidism.¹³ In addition, dose-related myelosuppression with isolated leukopenia, particularly neutropenia, also has been reported (18% of patients at a dosage of 300 mg/m²/d and 43% of patients with a dosage greater than 300 mg/m²/d). Leukopenia generally occurs within the first 4 to 8 weeks of treatment, is relatively mild (WBC, 1000–2999/µL), and generally is reversible.^13-15 One review of 66 mycosis fungoides patients treated with bexarotene described a patient who developed leukopenia 15 months after initiating bexarotene therapy.¹⁴ The manufacturer recommends that treatment with bexarotene be continued as long as the patient is receiving benefit from the treatment. One trial of 70 mycosis fungoides patient treated with bexarotene reported response rates of 48% on bexarotene monotherapy (n=54) and 69% on bexarotene plus an additional agent (n=16).¹⁵ The authors noted higher response rates in patients on 2 lipid-lowering agents. They concluded that bexarotene was a safe and effective agent for treatment of cutaneous T-cell lymphoma and recommended continued treatment with a lowered dose of bexarotene in those achieving complete responses for a period of 2 years. Although the recommended initial dose is 300 mg/m²/d, bexarotene can be increased to 400 mg/m²/d after 8 weeks if no response to treatment is appreciated.¹⁶ Our patient was on a maximum bexarotene dose of 600 mg once daily (280 mg/m²/d) for the first 2 years, and a maintenance dose of 300 mg once daily for the next 3 years. He was not on any medicines known to induce leukopenia and he was not given any known cytochrome P450 3A4 inhibitors that could increase the toxicity of bexarotene.

The patient’s CBC was checked routinely every 2 to 3 months after he was started on bexarotene. For 5 years, the CBC and differential remained within reference range; however, his CD4 counts were not followed during those 5 years. We attribute his CD4 lymphopenia and subsequent pneumocystis pneumonia to bexarotene. After our patient’s CD4 lymphopenia was discovered, he developed a precipitous drop in his WBC and lymphocyte counts while hospitalized that worsened over a 2-week period. At this point, the bexarotene was discontinued and his WBC count slowly recovered. We believe that one of the initial antibiotics prescribed by the patient’s primary care physician at initial onset of pneumonia symptoms as an outpatient could have acted synergistically with bexarotene to worsen lymphopenia. Specifically, ceftazidime, vancomycin, and ciprofloxacin have all been reported to cause leukopenia; however, it was neutropenia in these cases, not lymphopenia.^17,18 Notwithstanding, the opportunistic pneumonia and therefore CD4 lymphopenia was present prior to any antibiotic use.

The CD4 lymphopenia was unlikely due to underlying infection(s) because an extensive workup was negative, except for the pneumocystis, which likely resulted from the lymphopenia. The CD4 lymphopenia also could be idiopathic, as it has been reported in 3 patients with mycosis fungoides.¹⁹ All 3 patients were erythrodermic at presentation and were noted to have numerous CD4⁺ lymphocytes in the cutaneous lesions but few circulating CD4⁺ T lymphocytes in the blood. The authors attributed the CD4 lymphopenia to cutaneous sequestration of CD4⁺ T lymphocytes.¹⁹ These cases contrast with our patient who was in clinical remission at the time of CD4 lymphopenia, which improved and normalized following discontinuation of bexarotene.

Conclusion

This case emphasizes the importance of monitoring for leukopenia, specifically CD4 lymphopenia, in patients on long-term bexarotene therapy. Routine CBC as well as T-cell subset counts should be performed during treatment. Rotation off bexarotene after several years of therapy should be considered, even in patients with continuous benefit from this systemic therapy.

ORLANDO – A first-in-class antiviral drug was safe and effective when used to prevent clinically significant cytomegalovirus infections in adults undergoing hematopoietic cell transplantation.

At 24 weeks post-transplant, 38% (122/325) of those receiving the novel antiviral letermovir were considered treatment failures, compared with 61% (103/170) of those receiving placebo (P less than .0001). All-cause mortality was 10% (n=32/325) for patients receiving letermovir and 16%, (n=27/170) for the placebo group (log rank two-sided P = 0.0317).

CDC/Dr. Craig Lyerla

This article was updated 2/27/17.

[email protected]

On Twitter @karioakes

ORLANDO – A first-in-class antiviral drug was safe and effective when used to prevent clinically significant cytomegalovirus infections in adults undergoing hematopoietic cell transplantation.

At 24 weeks post-transplant, 38% (122/325) of those receiving the novel antiviral letermovir were considered treatment failures, compared with 61% (103/170) of those receiving placebo (P less than .0001). All-cause mortality was 10% (n=32/325) for patients receiving letermovir and 16%, (n=27/170) for the placebo group (log rank two-sided P = 0.0317).

CDC/Dr. Craig Lyerla

This article was updated 2/27/17.

[email protected]

On Twitter @karioakes

ORLANDO – A first-in-class antiviral drug was safe and effective when used to prevent clinically significant cytomegalovirus infections in adults undergoing hematopoietic cell transplantation.

At 24 weeks post-transplant, 38% (122/325) of those receiving the novel antiviral letermovir were considered treatment failures, compared with 61% (103/170) of those receiving placebo (P less than .0001). All-cause mortality was 10% (n=32/325) for patients receiving letermovir and 16%, (n=27/170) for the placebo group (log rank two-sided P = 0.0317).

CDC/Dr. Craig Lyerla

This article was updated 2/27/17.

[email protected]

On Twitter @karioakes

WAILEA, HAWAII – It is time for a new system of classifying nevi, according to Ashfaq Marghoob, MD, of Memorial Sloan Kettering Cancer Center, New York.

“It was known for the last 30 or 40 years that we do need to subclassify nevi into groups, so as to better stratify for melanoma risk,” identifying groups of individuals who would benefit most from targeted screening, Dr. Marghoob said in a video interview at the meeting, provided by Global Academy for Medical Education/Skin Disease Education Foundation. But it has been clear that there are many flaws in the current classification system, he added.

This is beginning to change as new data emerge about gene mutations and other science that can better stratify “or segregate” the nevi into subsets, and “the hope is we will be better able to predict which subsets are associated with melanoma risk either within the lesion itself or poses an increased risk to the patient,” he explained.

“As our understanding grows, we will start to come out with subsets of nevi that have a certain clinical and dermoscopic morphology,” to help predict which patients would benefit most from being monitored very closely, with the aim of detecting – and curing – melanomas early, said Dr. Marghoob, director of Memorial Sloan Kettering’s regional skin cancer clinic in Hauppauge, N.Y.

He had no financial conflicts to disclose.

SDEF and this news organization are owned by the same parent organization.

WAILEA, HAWAII – It is time for a new system of classifying nevi, according to Ashfaq Marghoob, MD, of Memorial Sloan Kettering Cancer Center, New York.

“It was known for the last 30 or 40 years that we do need to subclassify nevi into groups, so as to better stratify for melanoma risk,” identifying groups of individuals who would benefit most from targeted screening, Dr. Marghoob said in a video interview at the meeting, provided by Global Academy for Medical Education/Skin Disease Education Foundation. But it has been clear that there are many flaws in the current classification system, he added.

This is beginning to change as new data emerge about gene mutations and other science that can better stratify “or segregate” the nevi into subsets, and “the hope is we will be better able to predict which subsets are associated with melanoma risk either within the lesion itself or poses an increased risk to the patient,” he explained.

“As our understanding grows, we will start to come out with subsets of nevi that have a certain clinical and dermoscopic morphology,” to help predict which patients would benefit most from being monitored very closely, with the aim of detecting – and curing – melanomas early, said Dr. Marghoob, director of Memorial Sloan Kettering’s regional skin cancer clinic in Hauppauge, N.Y.

He had no financial conflicts to disclose.

SDEF and this news organization are owned by the same parent organization.

WAILEA, HAWAII – It is time for a new system of classifying nevi, according to Ashfaq Marghoob, MD, of Memorial Sloan Kettering Cancer Center, New York.

“It was known for the last 30 or 40 years that we do need to subclassify nevi into groups, so as to better stratify for melanoma risk,” identifying groups of individuals who would benefit most from targeted screening, Dr. Marghoob said in a video interview at the meeting, provided by Global Academy for Medical Education/Skin Disease Education Foundation. But it has been clear that there are many flaws in the current classification system, he added.

This is beginning to change as new data emerge about gene mutations and other science that can better stratify “or segregate” the nevi into subsets, and “the hope is we will be better able to predict which subsets are associated with melanoma risk either within the lesion itself or poses an increased risk to the patient,” he explained.

“As our understanding grows, we will start to come out with subsets of nevi that have a certain clinical and dermoscopic morphology,” to help predict which patients would benefit most from being monitored very closely, with the aim of detecting – and curing – melanomas early, said Dr. Marghoob, director of Memorial Sloan Kettering’s regional skin cancer clinic in Hauppauge, N.Y.

He had no financial conflicts to disclose.

SDEF and this news organization are owned by the same parent organization.

Progress continues to be made on creating a Zika vaccine, but taking any of the current candidates all the way through clinical trials and into production could take another few years, according to the latest information presented at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

“As we all know, there is no vaccine for Zika, but there are a number of vaccines that have been developed over the last century or so for other flaviviruses, [such as] dengue, yellow fever, Japanese encephalitis, [West Nile], and we know a great deal about flaviviruses in general and the pathology that they have,” explained Gerald R. Kovacs, PhD, of the Biomedical Advanced Research and Development Authority (BARDA). “What we’re doing is using our lessons learned and working with the epidemiologists, with the clinicians, with the nonclinical development people, and using those lessons to develop new vaccines for Zika.”

Aunt_Spray/Thinkstock

[email protected]

Progress continues to be made on creating a Zika vaccine, but taking any of the current candidates all the way through clinical trials and into production could take another few years, according to the latest information presented at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

“As we all know, there is no vaccine for Zika, but there are a number of vaccines that have been developed over the last century or so for other flaviviruses, [such as] dengue, yellow fever, Japanese encephalitis, [West Nile], and we know a great deal about flaviviruses in general and the pathology that they have,” explained Gerald R. Kovacs, PhD, of the Biomedical Advanced Research and Development Authority (BARDA). “What we’re doing is using our lessons learned and working with the epidemiologists, with the clinicians, with the nonclinical development people, and using those lessons to develop new vaccines for Zika.”

Aunt_Spray/Thinkstock

[email protected]

Progress continues to be made on creating a Zika vaccine, but taking any of the current candidates all the way through clinical trials and into production could take another few years, according to the latest information presented at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

“As we all know, there is no vaccine for Zika, but there are a number of vaccines that have been developed over the last century or so for other flaviviruses, [such as] dengue, yellow fever, Japanese encephalitis, [West Nile], and we know a great deal about flaviviruses in general and the pathology that they have,” explained Gerald R. Kovacs, PhD, of the Biomedical Advanced Research and Development Authority (BARDA). “What we’re doing is using our lessons learned and working with the epidemiologists, with the clinicians, with the nonclinical development people, and using those lessons to develop new vaccines for Zika.”

Aunt_Spray/Thinkstock

[email protected]