Pediatrics

Study authors Mary Relling

(left) and Chengcheng Liu

Photo courtesy of St. Jude

Children’s Research Hospital

and Peter Barta

Researchers have identified several factors that may increase the risk of asparaginase-induced pancreatitis in patients with acute lymphoblastic leukemia (ALL).

The team found that 16 variants in the CPA2 gene—and 1 rare variant in particular—were associated with a higher risk of asparaginase-induced pancreatitis.

Patients also had a higher risk if they had genetically defined Native American ancestry, were older, and received higher doses of asparaginase.

The researchers reported these findings in the Journal of Clinical Oncology.

“In this study, we identified several independent risk factors for asparaginase-induced pancreatitis and also gained insight into the mechanism responsible for this serious treatment complication,” said study author Mary Relling, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“Understanding the risk factors for acute pancreatitis is important because, in patients who can tolerate the drug, asparaginase reduces the likelihood that ALL patients will relapse.”

The research included 5398 ALL patients (ages 0 to 30) who were treated in clinical trials organized by St. Jude or the Children’s Oncology Group. In all, 188 patients developed pancreatitis at least once during ALL therapy.

To search for risk factors associated with asparaginase-induced pancreatitis, the researchers checked patient DNA for more than 920,000 gene variants.

The team also sequenced 283 genes, including genes associated with ALL risk and treatment outcome and genes linked to an elevated risk of pancreatitis in patients with different health problems.

The results revealed a rare nonsense variant in CPA2 (rs199695765) that yields a truncated version of the pancreatic enzyme proCPA2. The researchers said this variant was “highly associated” with pancreatitis, with a hazard ratio (HR) of 587 (P=9.0×10⁻⁹).

Two study participants each carried 1 copy of the variant, and both patients developed severe pancreatitis within weeks of receiving their first dose of asparaginase.

“That suggests patients with this rare variant cannot tolerate the drug long enough to benefit from treatment,” Dr Relling said. “For these patients, ALL treatment regimens that do not depend on asparaginase may be preferable.”

The researchers estimated that about 9 in 100,000 individuals carry the suspected high-risk CPA2 variant.

The team also found an excess of additional CPA2 variants in patients who developed pancreatitis compared to those who did not (P=0.001).

In all, the researchers identified 380 variants in CPA2. Sixteen of them were significantly associated (P<0.05) with pancreatitis, and 54% (13/24) of patients who carried at least 1 of these variants developed pancreatitis.

The researchers also found links between clinical factors and asparaginase-induced pancreatitis. A multivariate analysis suggested the following were associated with pancreatitis:

• Older age (HR=1.1 per year; P<0.001)
• Genetically defined Native American ancestry (HR=1.2 for every 10% increase in Native American ancestry; P<0.001)
• High-dose (≥240,000 U/m²) asparaginase regimens (HR=3.2; P<0.001).
  

Study authors Mary Relling

(left) and Chengcheng Liu

Photo courtesy of St. Jude

Children’s Research Hospital

and Peter Barta

Researchers have identified several factors that may increase the risk of asparaginase-induced pancreatitis in patients with acute lymphoblastic leukemia (ALL).

The team found that 16 variants in the CPA2 gene—and 1 rare variant in particular—were associated with a higher risk of asparaginase-induced pancreatitis.

Patients also had a higher risk if they had genetically defined Native American ancestry, were older, and received higher doses of asparaginase.

The researchers reported these findings in the Journal of Clinical Oncology.

“In this study, we identified several independent risk factors for asparaginase-induced pancreatitis and also gained insight into the mechanism responsible for this serious treatment complication,” said study author Mary Relling, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“Understanding the risk factors for acute pancreatitis is important because, in patients who can tolerate the drug, asparaginase reduces the likelihood that ALL patients will relapse.”

The research included 5398 ALL patients (ages 0 to 30) who were treated in clinical trials organized by St. Jude or the Children’s Oncology Group. In all, 188 patients developed pancreatitis at least once during ALL therapy.

To search for risk factors associated with asparaginase-induced pancreatitis, the researchers checked patient DNA for more than 920,000 gene variants.

The team also sequenced 283 genes, including genes associated with ALL risk and treatment outcome and genes linked to an elevated risk of pancreatitis in patients with different health problems.

The results revealed a rare nonsense variant in CPA2 (rs199695765) that yields a truncated version of the pancreatic enzyme proCPA2. The researchers said this variant was “highly associated” with pancreatitis, with a hazard ratio (HR) of 587 (P=9.0×10⁻⁹).

Two study participants each carried 1 copy of the variant, and both patients developed severe pancreatitis within weeks of receiving their first dose of asparaginase.

“That suggests patients with this rare variant cannot tolerate the drug long enough to benefit from treatment,” Dr Relling said. “For these patients, ALL treatment regimens that do not depend on asparaginase may be preferable.”

The researchers estimated that about 9 in 100,000 individuals carry the suspected high-risk CPA2 variant.

The team also found an excess of additional CPA2 variants in patients who developed pancreatitis compared to those who did not (P=0.001).

In all, the researchers identified 380 variants in CPA2. Sixteen of them were significantly associated (P<0.05) with pancreatitis, and 54% (13/24) of patients who carried at least 1 of these variants developed pancreatitis.

The researchers also found links between clinical factors and asparaginase-induced pancreatitis. A multivariate analysis suggested the following were associated with pancreatitis:

• Older age (HR=1.1 per year; P<0.001)
• Genetically defined Native American ancestry (HR=1.2 for every 10% increase in Native American ancestry; P<0.001)
• High-dose (≥240,000 U/m²) asparaginase regimens (HR=3.2; P<0.001).
  

Study authors Mary Relling

(left) and Chengcheng Liu

Photo courtesy of St. Jude

Children’s Research Hospital

and Peter Barta

Researchers have identified several factors that may increase the risk of asparaginase-induced pancreatitis in patients with acute lymphoblastic leukemia (ALL).

The team found that 16 variants in the CPA2 gene—and 1 rare variant in particular—were associated with a higher risk of asparaginase-induced pancreatitis.

Patients also had a higher risk if they had genetically defined Native American ancestry, were older, and received higher doses of asparaginase.

The researchers reported these findings in the Journal of Clinical Oncology.

“In this study, we identified several independent risk factors for asparaginase-induced pancreatitis and also gained insight into the mechanism responsible for this serious treatment complication,” said study author Mary Relling, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“Understanding the risk factors for acute pancreatitis is important because, in patients who can tolerate the drug, asparaginase reduces the likelihood that ALL patients will relapse.”

The research included 5398 ALL patients (ages 0 to 30) who were treated in clinical trials organized by St. Jude or the Children’s Oncology Group. In all, 188 patients developed pancreatitis at least once during ALL therapy.

To search for risk factors associated with asparaginase-induced pancreatitis, the researchers checked patient DNA for more than 920,000 gene variants.

The team also sequenced 283 genes, including genes associated with ALL risk and treatment outcome and genes linked to an elevated risk of pancreatitis in patients with different health problems.

The results revealed a rare nonsense variant in CPA2 (rs199695765) that yields a truncated version of the pancreatic enzyme proCPA2. The researchers said this variant was “highly associated” with pancreatitis, with a hazard ratio (HR) of 587 (P=9.0×10⁻⁹).

Two study participants each carried 1 copy of the variant, and both patients developed severe pancreatitis within weeks of receiving their first dose of asparaginase.

“That suggests patients with this rare variant cannot tolerate the drug long enough to benefit from treatment,” Dr Relling said. “For these patients, ALL treatment regimens that do not depend on asparaginase may be preferable.”

The researchers estimated that about 9 in 100,000 individuals carry the suspected high-risk CPA2 variant.

The team also found an excess of additional CPA2 variants in patients who developed pancreatitis compared to those who did not (P=0.001).

In all, the researchers identified 380 variants in CPA2. Sixteen of them were significantly associated (P<0.05) with pancreatitis, and 54% (13/24) of patients who carried at least 1 of these variants developed pancreatitis.

The researchers also found links between clinical factors and asparaginase-induced pancreatitis. A multivariate analysis suggested the following were associated with pancreatitis:

• Older age (HR=1.1 per year; P<0.001)
• Genetically defined Native American ancestry (HR=1.2 for every 10% increase in Native American ancestry; P<0.001)
• High-dose (≥240,000 U/m²) asparaginase regimens (HR=3.2; P<0.001).
  

The term “psychotherapy” describes a variety of talk-based treatments for psychiatric illnesses. Its fundamental premise is that there are determinants of mood, anxiety, and behavior that are not fully in our conscious awareness. By becoming more aware or by developing skills in managing thoughts and feelings, patients can get relief from symptoms that often impair functioning. The focus on unconscious thoughts, feelings, and behaviors is the central principle of dynamic psychotherapy in which the therapist listens to the patients speak freely about important people and events in their day-to-day lives and takes note of themes that emerge. Eventually they offer “interpretations” to their patients about these patterns, and ways that current problems may connect to powerful experiences from their earlier lives.

Dynamic psychotherapy is often contrasted with supportive psychotherapy. This is not cheerleading, but instead refers to supporting the healthy ability to think about oneself, one’s thoughts and emotions, and one’s needs, and the tension that these can create with the expectations of society. In working with children and adolescents, therapists are almost always supporting the age-appropriate development of some of these skills, particularly if a child has gotten developmentally stuck because of depressive, anxious, or attentional symptoms. There are almost always supportive elements in psychotherapy with a school-age or teenage child.

For children with anxiety disorders or mild to moderate depression, cognitive-behavioral therapy (CBT) is an evidence-based first-line treatment. CBT is a structured psychotherapy that helps patients to identify specific thoughts that trigger or follow their mood or anxiety symptoms, and then sets about establishing new (less-distorted) thoughts or practicing avoided behaviors to help learn new responses. It appears to be especially effective for anxiety disorders (such as social phobia, panic disorder, and generalized anxiety disorder) and for obsessive-compulsive disorder. There are specialized types of CBT that can be offered to patients (including children) who have been exposed to trauma and even for teenagers experiencing psychotic symptoms. It should be noted that one of the reasons that CBT has a robust evidence base supporting its use is that it is one of the most structured types of psychotherapy. It is standardized, reproducible, and easier to study than most other varieties of psychotherapy. Practicing CBT requires specific training, so in looking for a CBT therapist, one needs to ask whether she is CBT trained, and even whether she is trained in the type of CBT specific for the disorder you are treating.

A relative of CBT is dialectical behavioral therapy or DBT, developed to treat borderline personality disorder, a maladaptive pattern of identity uncertainty, emotional instability, and impulsivity that often starts in adolescence, causing stormy relationships and poor self-regulation that can contribute to self-injury, substance abuse, and chronic suicidality. DBT focuses on cognitive patterns, and utilizes a patient’s strengths to build new skills at managing challenging thoughts and feelings. The “dialectic” relates to interpersonal relationships, as this is where these patients often have great difficulty. High-quality DBT is often done with both individual and group therapy sessions. There is substantial evidence supporting the efficacy of this therapy in patients with borderline personality disorder.

Play therapy generally refers to the use of play (with toys, dolls, art, or games) in therapy with the youngest children. Such young children are unlikely to speak in a fluid manner about their relationships or struggles, as they may lack some of the cognitive means to be self-reflective. So instead, a therapist will watch for themes in their play (aggression, cheating, repetitive stories with dolls or art) that may reflect important themes, that they will then work on in play or in speaking, as tolerated. Therapists of older children also may use play to help these children feel more comfortable as they proceed with CBT or another talk therapy.

While gathering data from parents is always part of therapy for children, family therapy brings the whole family into a room with the therapist, who focuses on the roles each person may play in the family and patterns of communication (verbal and otherwise) that may be contributing to a young person’s symptoms. Family therapy can be very important in treating anorexia nervosa, somatoform illnesses, and conduct disorder in children and adolescents. While it can be a complex type of therapy to study, there is significant evidence supporting its efficacy in these very challenging disorders of youth.

There is a growing body of evidence in adults demonstrating neuroimaging changes after effective psychotherapies. Several studies of patients with OCD who were successfully treated with CBT have demonstrated decreased metabolism in the right caudate nucleus, and those treated effectively for phobias showed decreased activity in the limbic and paralimbic areas. Interestingly, patients with OCD and phobias who were effectively treated with selective serotonin reuptake inhibitors demonstrated these same changes on functional neuroimaging (Mol Psychiatry. 2006 Jun;11[6]:528-38.). An Italian meta-analysis of patients treated for major depression with medications (usually selective serotonin reuptake inhibitors) or with psychotherapy (usually CBT) demonstrated different, and possibly complementary brain changes in the two treatment groups (Brain Imaging Behav. 2015 Jul 12. [Epub ahead of print]). With time, these studies may help us to better understand the nature of specific illnesses and more about neuroplasticity, and may even help us to understand when medications, therapy, or both are indicated.

©AlexRaths/Thinkstock

Finally, it is worth noting that multiple studies indicate that one of the most consistent predictors of a positive outcome in psychotherapy is the presence of a strong treatment alliance between the therapist and the patient. Studies have demonstrated that a strong alliance was a better predictor of positive outcomes than type of psychotherapy, and seemed to be a strong predictor of positive outcomes even in cases where the treatment was pharmacologic. This makes it critical that when you are trying to help your patient find a “good therapist,” you consider whether the patient may need a specialized therapy (CBT, DBT, or family therapy). But you should also instruct your patient and their parents that it is very important that they like their therapist, that after several meetings they should feel comfortable meeting and talking honestly with him, and that they should feel that the therapist cares about them and is committed to their health and well-being.

Dr. Swick is an attending psychiatrist in the division of child psychiatry at Massachusetts General Hospital, Boston, and director of the Parenting at a Challenging Time (PACT) Program at the Vernon Cancer Center at Newton (Mass.) Wellesley Hospital. Dr. Jellinek is professor of psychiatry and of pediatrics at Harvard Medical School, Boston. Email them at pdnews@frontlinemedcom.com.

The term “psychotherapy” describes a variety of talk-based treatments for psychiatric illnesses. Its fundamental premise is that there are determinants of mood, anxiety, and behavior that are not fully in our conscious awareness. By becoming more aware or by developing skills in managing thoughts and feelings, patients can get relief from symptoms that often impair functioning. The focus on unconscious thoughts, feelings, and behaviors is the central principle of dynamic psychotherapy in which the therapist listens to the patients speak freely about important people and events in their day-to-day lives and takes note of themes that emerge. Eventually they offer “interpretations” to their patients about these patterns, and ways that current problems may connect to powerful experiences from their earlier lives.

Dynamic psychotherapy is often contrasted with supportive psychotherapy. This is not cheerleading, but instead refers to supporting the healthy ability to think about oneself, one’s thoughts and emotions, and one’s needs, and the tension that these can create with the expectations of society. In working with children and adolescents, therapists are almost always supporting the age-appropriate development of some of these skills, particularly if a child has gotten developmentally stuck because of depressive, anxious, or attentional symptoms. There are almost always supportive elements in psychotherapy with a school-age or teenage child.

For children with anxiety disorders or mild to moderate depression, cognitive-behavioral therapy (CBT) is an evidence-based first-line treatment. CBT is a structured psychotherapy that helps patients to identify specific thoughts that trigger or follow their mood or anxiety symptoms, and then sets about establishing new (less-distorted) thoughts or practicing avoided behaviors to help learn new responses. It appears to be especially effective for anxiety disorders (such as social phobia, panic disorder, and generalized anxiety disorder) and for obsessive-compulsive disorder. There are specialized types of CBT that can be offered to patients (including children) who have been exposed to trauma and even for teenagers experiencing psychotic symptoms. It should be noted that one of the reasons that CBT has a robust evidence base supporting its use is that it is one of the most structured types of psychotherapy. It is standardized, reproducible, and easier to study than most other varieties of psychotherapy. Practicing CBT requires specific training, so in looking for a CBT therapist, one needs to ask whether she is CBT trained, and even whether she is trained in the type of CBT specific for the disorder you are treating.

A relative of CBT is dialectical behavioral therapy or DBT, developed to treat borderline personality disorder, a maladaptive pattern of identity uncertainty, emotional instability, and impulsivity that often starts in adolescence, causing stormy relationships and poor self-regulation that can contribute to self-injury, substance abuse, and chronic suicidality. DBT focuses on cognitive patterns, and utilizes a patient’s strengths to build new skills at managing challenging thoughts and feelings. The “dialectic” relates to interpersonal relationships, as this is where these patients often have great difficulty. High-quality DBT is often done with both individual and group therapy sessions. There is substantial evidence supporting the efficacy of this therapy in patients with borderline personality disorder.

Play therapy generally refers to the use of play (with toys, dolls, art, or games) in therapy with the youngest children. Such young children are unlikely to speak in a fluid manner about their relationships or struggles, as they may lack some of the cognitive means to be self-reflective. So instead, a therapist will watch for themes in their play (aggression, cheating, repetitive stories with dolls or art) that may reflect important themes, that they will then work on in play or in speaking, as tolerated. Therapists of older children also may use play to help these children feel more comfortable as they proceed with CBT or another talk therapy.

While gathering data from parents is always part of therapy for children, family therapy brings the whole family into a room with the therapist, who focuses on the roles each person may play in the family and patterns of communication (verbal and otherwise) that may be contributing to a young person’s symptoms. Family therapy can be very important in treating anorexia nervosa, somatoform illnesses, and conduct disorder in children and adolescents. While it can be a complex type of therapy to study, there is significant evidence supporting its efficacy in these very challenging disorders of youth.

There is a growing body of evidence in adults demonstrating neuroimaging changes after effective psychotherapies. Several studies of patients with OCD who were successfully treated with CBT have demonstrated decreased metabolism in the right caudate nucleus, and those treated effectively for phobias showed decreased activity in the limbic and paralimbic areas. Interestingly, patients with OCD and phobias who were effectively treated with selective serotonin reuptake inhibitors demonstrated these same changes on functional neuroimaging (Mol Psychiatry. 2006 Jun;11[6]:528-38.). An Italian meta-analysis of patients treated for major depression with medications (usually selective serotonin reuptake inhibitors) or with psychotherapy (usually CBT) demonstrated different, and possibly complementary brain changes in the two treatment groups (Brain Imaging Behav. 2015 Jul 12. [Epub ahead of print]). With time, these studies may help us to better understand the nature of specific illnesses and more about neuroplasticity, and may even help us to understand when medications, therapy, or both are indicated.

©AlexRaths/Thinkstock

Finally, it is worth noting that multiple studies indicate that one of the most consistent predictors of a positive outcome in psychotherapy is the presence of a strong treatment alliance between the therapist and the patient. Studies have demonstrated that a strong alliance was a better predictor of positive outcomes than type of psychotherapy, and seemed to be a strong predictor of positive outcomes even in cases where the treatment was pharmacologic. This makes it critical that when you are trying to help your patient find a “good therapist,” you consider whether the patient may need a specialized therapy (CBT, DBT, or family therapy). But you should also instruct your patient and their parents that it is very important that they like their therapist, that after several meetings they should feel comfortable meeting and talking honestly with him, and that they should feel that the therapist cares about them and is committed to their health and well-being.

Dr. Swick is an attending psychiatrist in the division of child psychiatry at Massachusetts General Hospital, Boston, and director of the Parenting at a Challenging Time (PACT) Program at the Vernon Cancer Center at Newton (Mass.) Wellesley Hospital. Dr. Jellinek is professor of psychiatry and of pediatrics at Harvard Medical School, Boston. Email them at pdnews@frontlinemedcom.com.

The term “psychotherapy” describes a variety of talk-based treatments for psychiatric illnesses. Its fundamental premise is that there are determinants of mood, anxiety, and behavior that are not fully in our conscious awareness. By becoming more aware or by developing skills in managing thoughts and feelings, patients can get relief from symptoms that often impair functioning. The focus on unconscious thoughts, feelings, and behaviors is the central principle of dynamic psychotherapy in which the therapist listens to the patients speak freely about important people and events in their day-to-day lives and takes note of themes that emerge. Eventually they offer “interpretations” to their patients about these patterns, and ways that current problems may connect to powerful experiences from their earlier lives.

Dynamic psychotherapy is often contrasted with supportive psychotherapy. This is not cheerleading, but instead refers to supporting the healthy ability to think about oneself, one’s thoughts and emotions, and one’s needs, and the tension that these can create with the expectations of society. In working with children and adolescents, therapists are almost always supporting the age-appropriate development of some of these skills, particularly if a child has gotten developmentally stuck because of depressive, anxious, or attentional symptoms. There are almost always supportive elements in psychotherapy with a school-age or teenage child.

For children with anxiety disorders or mild to moderate depression, cognitive-behavioral therapy (CBT) is an evidence-based first-line treatment. CBT is a structured psychotherapy that helps patients to identify specific thoughts that trigger or follow their mood or anxiety symptoms, and then sets about establishing new (less-distorted) thoughts or practicing avoided behaviors to help learn new responses. It appears to be especially effective for anxiety disorders (such as social phobia, panic disorder, and generalized anxiety disorder) and for obsessive-compulsive disorder. There are specialized types of CBT that can be offered to patients (including children) who have been exposed to trauma and even for teenagers experiencing psychotic symptoms. It should be noted that one of the reasons that CBT has a robust evidence base supporting its use is that it is one of the most structured types of psychotherapy. It is standardized, reproducible, and easier to study than most other varieties of psychotherapy. Practicing CBT requires specific training, so in looking for a CBT therapist, one needs to ask whether she is CBT trained, and even whether she is trained in the type of CBT specific for the disorder you are treating.

A relative of CBT is dialectical behavioral therapy or DBT, developed to treat borderline personality disorder, a maladaptive pattern of identity uncertainty, emotional instability, and impulsivity that often starts in adolescence, causing stormy relationships and poor self-regulation that can contribute to self-injury, substance abuse, and chronic suicidality. DBT focuses on cognitive patterns, and utilizes a patient’s strengths to build new skills at managing challenging thoughts and feelings. The “dialectic” relates to interpersonal relationships, as this is where these patients often have great difficulty. High-quality DBT is often done with both individual and group therapy sessions. There is substantial evidence supporting the efficacy of this therapy in patients with borderline personality disorder.

Play therapy generally refers to the use of play (with toys, dolls, art, or games) in therapy with the youngest children. Such young children are unlikely to speak in a fluid manner about their relationships or struggles, as they may lack some of the cognitive means to be self-reflective. So instead, a therapist will watch for themes in their play (aggression, cheating, repetitive stories with dolls or art) that may reflect important themes, that they will then work on in play or in speaking, as tolerated. Therapists of older children also may use play to help these children feel more comfortable as they proceed with CBT or another talk therapy.

While gathering data from parents is always part of therapy for children, family therapy brings the whole family into a room with the therapist, who focuses on the roles each person may play in the family and patterns of communication (verbal and otherwise) that may be contributing to a young person’s symptoms. Family therapy can be very important in treating anorexia nervosa, somatoform illnesses, and conduct disorder in children and adolescents. While it can be a complex type of therapy to study, there is significant evidence supporting its efficacy in these very challenging disorders of youth.

There is a growing body of evidence in adults demonstrating neuroimaging changes after effective psychotherapies. Several studies of patients with OCD who were successfully treated with CBT have demonstrated decreased metabolism in the right caudate nucleus, and those treated effectively for phobias showed decreased activity in the limbic and paralimbic areas. Interestingly, patients with OCD and phobias who were effectively treated with selective serotonin reuptake inhibitors demonstrated these same changes on functional neuroimaging (Mol Psychiatry. 2006 Jun;11[6]:528-38.). An Italian meta-analysis of patients treated for major depression with medications (usually selective serotonin reuptake inhibitors) or with psychotherapy (usually CBT) demonstrated different, and possibly complementary brain changes in the two treatment groups (Brain Imaging Behav. 2015 Jul 12. [Epub ahead of print]). With time, these studies may help us to better understand the nature of specific illnesses and more about neuroplasticity, and may even help us to understand when medications, therapy, or both are indicated.

©AlexRaths/Thinkstock

Finally, it is worth noting that multiple studies indicate that one of the most consistent predictors of a positive outcome in psychotherapy is the presence of a strong treatment alliance between the therapist and the patient. Studies have demonstrated that a strong alliance was a better predictor of positive outcomes than type of psychotherapy, and seemed to be a strong predictor of positive outcomes even in cases where the treatment was pharmacologic. This makes it critical that when you are trying to help your patient find a “good therapist,” you consider whether the patient may need a specialized therapy (CBT, DBT, or family therapy). But you should also instruct your patient and their parents that it is very important that they like their therapist, that after several meetings they should feel comfortable meeting and talking honestly with him, and that they should feel that the therapist cares about them and is committed to their health and well-being.

Dr. Swick is an attending psychiatrist in the division of child psychiatry at Massachusetts General Hospital, Boston, and director of the Parenting at a Challenging Time (PACT) Program at the Vernon Cancer Center at Newton (Mass.) Wellesley Hospital. Dr. Jellinek is professor of psychiatry and of pediatrics at Harvard Medical School, Boston. Email them at pdnews@frontlinemedcom.com.

LOS ANGELES – For patients with severe atopic dermatitis and their families and treating physicians, there is big news: finally, there is light at the end of the tunnel, Dr. Lisa A. Beck declared in a plenary lecture at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

Better drugs are on the way. The new agents in the developmental pipeline target specific immunologic pathways that appear to be central to atopic dermatitis. Moreover, exciting recent evidence indicates it’s possible to noninvasively identify children at high risk for atopic dermatitis and intervene preventively to reduce the likelihood of actually developing the disease, according to Dr. Beck, professor of dermatology and medicine at the University of Rochester (N.Y.).

Bruce Jancin/Frontline Medical News

“Many pharmaceutical companies have now turned their attention to atopic dermatitis and aren’t just focusing on asthma anymore. The biggest pipeline appears to involve drugs that might target the Th2 [T helper 2 cells] pathway, either by trying to eliminate alarmins such as TSLP [thymic stromal lymphopoietin], or reverse the effects of the Th2 cytokines interleukin-4 and -13, either alone or together, or prevent the recruitment of activated T cells,” she said.

Dr. Beck presented an update on three such promising investigational approaches on the horizon: the IL-4 and IL-13 inhibitor dupilumab; oral and topical Janus associated kinase (JAK) inhibitors; and anti-IgE therapies.

Dupilumab: This fully human monoclonal antibody that blocks IL-4 and IL-13 is also being developed as a treatment for eosinophilic asthma. Dr. Beck was first author of a report on a series of four phase II randomized trials of dupilumab for moderate to severe atopic dermatitis in adults. The publication caused a stir, with dupilumab-treated patients showing marked and rapid improvement to a degree previously unseen in the treatment of this disease (N Engl J Med. 2014;371[2]:130-9).

In the 12-week study, for example, 85% of dupilumab-treated patients achieved at least a 50% improvement in the Eczema Area and Severity Index (EASI) score, compared with 35% of placebo-treated controls, with a significant between-group difference seen in the first week. Maximum improvement – a 75%-80% reduction in EASI scores – was noted at 6-8 weeks. Forty percent of dupilumab-treated patients achieved clear or near-clear skin by investigator’s global assessment, compared with just 7% of controls.

Itching decreased markedly beginning in the first week, too. The investigational agent’s side effect profile was similar to placebo. Phase III clinical trials in atopic dermatitis are ongoing.

A study by other investigators found that dupilumab resulted in rapid improvement in the molecular signature of atopic dermatitis in skin biopsy specimens (J Allergy Clin Immunol. 2014 Dec;134[6]:1293-300). The observed changes in gene expression suggest that dupilumab might have a beneficial effect on the dysfunctional skin barrier that is a hallmark of atopic dermatitis. Further studies are now being planned to take a closer look at that possibility.

JAK inhibitors: “We’re all really excited about this approach because dogs, too, get allergic dermatitis, and in 2013 a JAK 1 and 3 inhibitor [oclacitinib, Apoquel] was approved as a veterinary medicine therapy. It has resulted in dramatic improvement in itch within 1 week of administration, as well as significant improvement in the dermatitis,” Dr. Beck said.

Three JAK inhibitors are now in phase II clinical trials for atopic dermatitis in humans: the JAK 1 and 3 inhibitor tofacitinib (Xeljanz), both as a topical ointment and the familiar oral formulation; baricitinib, an oral JAK 1 and 2 inhibitor; and an agent known for now as PF-04965842, which is an oral inhibitor specifically of JAK 1.

“JAK inhibitors have been quite effective in treating a number of other inflammatory conditions, as well as cancers. I think they will have a role in the treatment of atopic dermatitis. The biggest concerns will be the off-target effects,” she predicted.

Anti-IgE agents: Omalizumab (Xolair), a humanized monoclonal antibody that binds to IgE, has gotten mixed reviews as an investigational treatment for atopic dermatitis. The best study to date, a randomized, single-center, placebo-controlled, double-blind, 16-week clinical trial, found that omalizumab depleted IgE but didn’t improve the clinical course of atopic dermatitis (J Dtsch Dermatol Ges. 2010 Dec;8[12]:990-8). Nonetheless, a phase II trial of omalizumab is ongoing. Plus, ligelizumab, an anti-IgE monoclonal antibody with a higher affinity for IgE than omalizumab, is also in a phase II trial for adult atopic dermatitis.

“Anti-IgE therapy, I think, is still not dead in atopic dermatitis. I look forward to seeing whether omalizumab will work in unique subsets of patients, or whether a more potent anti-IgE molecule will be more beneficial,” Dr. Beck commented.

As exciting as the prospects are for these investigational agents, there also have been several recent important advances in the prevention of atopic dermatitis, she continued. Investigators led by Dr. Alan D. Irvine of Trinity College, Dublin, noninvasively measured transepidermal water loss in early infancy in more than 1,900 Irish 2-day-old infants and found that those in the 75th percentile for this early marker of skin barrier dysfunction were at 3.1-fold increased risk for diagnosis of atopic dermatitis by age 2 years (J Allergy Clin Immunol. 2016 Apr;137[4]:1111-6). This new-found ability to identify at-risk infants will be extremely helpful in designing atopic dermatitis prevention studies, according to Dr. Beck.

The other advance in prevention was provided via a randomized trial by Dr. Eric L. Simpson of Oregon Health and Science University, Portland, and his coinvestigators. They randomized a group of infants at high risk for atopic dermatitis to daily application of any of five OTC skin moisturizers or a no-moisturizer control group from 2 weeks through 6 months of age. The study hypothesis was that the moisturizers would help reverse the skin barrier abnormalities that play a key role in atopic dermatitis. The hypothesis was borne out by the finding that there was at least a 50% reduction in physician-diagnosed atopic dermatitis by age 6 months in the daily moisturizer group (J Allergy Clin Immunol. 2014 Oct;134[4]:818-23).

Dr. Beck concluded by describing a likely near-term atopic dermatitis prevention and management scenario: High-risk infants will be identified on the basis of noninvasive assessment of epithelial features, such as transepidermal water loss or the presence of high levels of thymic stromal lymphopoietin on the skin surface. Encouragement of daily moisturizing for these high-risk infants will prevent some of them from going on to develop eczema.

For those who do get eczema, dilute bleach baths will help in restoring normal skin barrier function, as was confirmed in an in-press study by Dr. Beck and her coinvestigators, who found that 46% of a group of adults with atopic dermatitis experienced at least a 50% improvement in EASI scores, a big improvement in itch, and reduced transepidermal water loss after 12 weeks of the bleach baths. As other investigators have reported, the bleach baths were very well tolerated and safe.

Dr. Beck reported serving as a consultant to eight pharmaceutical companies with an interest in developing new treatments for atopic dermatitis.

bjancin@frontlinemedcom.com

LOS ANGELES – For patients with severe atopic dermatitis and their families and treating physicians, there is big news: finally, there is light at the end of the tunnel, Dr. Lisa A. Beck declared in a plenary lecture at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

Better drugs are on the way. The new agents in the developmental pipeline target specific immunologic pathways that appear to be central to atopic dermatitis. Moreover, exciting recent evidence indicates it’s possible to noninvasively identify children at high risk for atopic dermatitis and intervene preventively to reduce the likelihood of actually developing the disease, according to Dr. Beck, professor of dermatology and medicine at the University of Rochester (N.Y.).

Bruce Jancin/Frontline Medical News

“Many pharmaceutical companies have now turned their attention to atopic dermatitis and aren’t just focusing on asthma anymore. The biggest pipeline appears to involve drugs that might target the Th2 [T helper 2 cells] pathway, either by trying to eliminate alarmins such as TSLP [thymic stromal lymphopoietin], or reverse the effects of the Th2 cytokines interleukin-4 and -13, either alone or together, or prevent the recruitment of activated T cells,” she said.

Dr. Beck presented an update on three such promising investigational approaches on the horizon: the IL-4 and IL-13 inhibitor dupilumab; oral and topical Janus associated kinase (JAK) inhibitors; and anti-IgE therapies.

Dupilumab: This fully human monoclonal antibody that blocks IL-4 and IL-13 is also being developed as a treatment for eosinophilic asthma. Dr. Beck was first author of a report on a series of four phase II randomized trials of dupilumab for moderate to severe atopic dermatitis in adults. The publication caused a stir, with dupilumab-treated patients showing marked and rapid improvement to a degree previously unseen in the treatment of this disease (N Engl J Med. 2014;371[2]:130-9).

In the 12-week study, for example, 85% of dupilumab-treated patients achieved at least a 50% improvement in the Eczema Area and Severity Index (EASI) score, compared with 35% of placebo-treated controls, with a significant between-group difference seen in the first week. Maximum improvement – a 75%-80% reduction in EASI scores – was noted at 6-8 weeks. Forty percent of dupilumab-treated patients achieved clear or near-clear skin by investigator’s global assessment, compared with just 7% of controls.

Itching decreased markedly beginning in the first week, too. The investigational agent’s side effect profile was similar to placebo. Phase III clinical trials in atopic dermatitis are ongoing.

A study by other investigators found that dupilumab resulted in rapid improvement in the molecular signature of atopic dermatitis in skin biopsy specimens (J Allergy Clin Immunol. 2014 Dec;134[6]:1293-300). The observed changes in gene expression suggest that dupilumab might have a beneficial effect on the dysfunctional skin barrier that is a hallmark of atopic dermatitis. Further studies are now being planned to take a closer look at that possibility.

JAK inhibitors: “We’re all really excited about this approach because dogs, too, get allergic dermatitis, and in 2013 a JAK 1 and 3 inhibitor [oclacitinib, Apoquel] was approved as a veterinary medicine therapy. It has resulted in dramatic improvement in itch within 1 week of administration, as well as significant improvement in the dermatitis,” Dr. Beck said.

Three JAK inhibitors are now in phase II clinical trials for atopic dermatitis in humans: the JAK 1 and 3 inhibitor tofacitinib (Xeljanz), both as a topical ointment and the familiar oral formulation; baricitinib, an oral JAK 1 and 2 inhibitor; and an agent known for now as PF-04965842, which is an oral inhibitor specifically of JAK 1.

“JAK inhibitors have been quite effective in treating a number of other inflammatory conditions, as well as cancers. I think they will have a role in the treatment of atopic dermatitis. The biggest concerns will be the off-target effects,” she predicted.

Anti-IgE agents: Omalizumab (Xolair), a humanized monoclonal antibody that binds to IgE, has gotten mixed reviews as an investigational treatment for atopic dermatitis. The best study to date, a randomized, single-center, placebo-controlled, double-blind, 16-week clinical trial, found that omalizumab depleted IgE but didn’t improve the clinical course of atopic dermatitis (J Dtsch Dermatol Ges. 2010 Dec;8[12]:990-8). Nonetheless, a phase II trial of omalizumab is ongoing. Plus, ligelizumab, an anti-IgE monoclonal antibody with a higher affinity for IgE than omalizumab, is also in a phase II trial for adult atopic dermatitis.

“Anti-IgE therapy, I think, is still not dead in atopic dermatitis. I look forward to seeing whether omalizumab will work in unique subsets of patients, or whether a more potent anti-IgE molecule will be more beneficial,” Dr. Beck commented.

As exciting as the prospects are for these investigational agents, there also have been several recent important advances in the prevention of atopic dermatitis, she continued. Investigators led by Dr. Alan D. Irvine of Trinity College, Dublin, noninvasively measured transepidermal water loss in early infancy in more than 1,900 Irish 2-day-old infants and found that those in the 75th percentile for this early marker of skin barrier dysfunction were at 3.1-fold increased risk for diagnosis of atopic dermatitis by age 2 years (J Allergy Clin Immunol. 2016 Apr;137[4]:1111-6). This new-found ability to identify at-risk infants will be extremely helpful in designing atopic dermatitis prevention studies, according to Dr. Beck.

The other advance in prevention was provided via a randomized trial by Dr. Eric L. Simpson of Oregon Health and Science University, Portland, and his coinvestigators. They randomized a group of infants at high risk for atopic dermatitis to daily application of any of five OTC skin moisturizers or a no-moisturizer control group from 2 weeks through 6 months of age. The study hypothesis was that the moisturizers would help reverse the skin barrier abnormalities that play a key role in atopic dermatitis. The hypothesis was borne out by the finding that there was at least a 50% reduction in physician-diagnosed atopic dermatitis by age 6 months in the daily moisturizer group (J Allergy Clin Immunol. 2014 Oct;134[4]:818-23).

Dr. Beck concluded by describing a likely near-term atopic dermatitis prevention and management scenario: High-risk infants will be identified on the basis of noninvasive assessment of epithelial features, such as transepidermal water loss or the presence of high levels of thymic stromal lymphopoietin on the skin surface. Encouragement of daily moisturizing for these high-risk infants will prevent some of them from going on to develop eczema.

For those who do get eczema, dilute bleach baths will help in restoring normal skin barrier function, as was confirmed in an in-press study by Dr. Beck and her coinvestigators, who found that 46% of a group of adults with atopic dermatitis experienced at least a 50% improvement in EASI scores, a big improvement in itch, and reduced transepidermal water loss after 12 weeks of the bleach baths. As other investigators have reported, the bleach baths were very well tolerated and safe.

Dr. Beck reported serving as a consultant to eight pharmaceutical companies with an interest in developing new treatments for atopic dermatitis.

bjancin@frontlinemedcom.com

LOS ANGELES – For patients with severe atopic dermatitis and their families and treating physicians, there is big news: finally, there is light at the end of the tunnel, Dr. Lisa A. Beck declared in a plenary lecture at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

Better drugs are on the way. The new agents in the developmental pipeline target specific immunologic pathways that appear to be central to atopic dermatitis. Moreover, exciting recent evidence indicates it’s possible to noninvasively identify children at high risk for atopic dermatitis and intervene preventively to reduce the likelihood of actually developing the disease, according to Dr. Beck, professor of dermatology and medicine at the University of Rochester (N.Y.).

Bruce Jancin/Frontline Medical News

“Many pharmaceutical companies have now turned their attention to atopic dermatitis and aren’t just focusing on asthma anymore. The biggest pipeline appears to involve drugs that might target the Th2 [T helper 2 cells] pathway, either by trying to eliminate alarmins such as TSLP [thymic stromal lymphopoietin], or reverse the effects of the Th2 cytokines interleukin-4 and -13, either alone or together, or prevent the recruitment of activated T cells,” she said.

Dr. Beck presented an update on three such promising investigational approaches on the horizon: the IL-4 and IL-13 inhibitor dupilumab; oral and topical Janus associated kinase (JAK) inhibitors; and anti-IgE therapies.

Dupilumab: This fully human monoclonal antibody that blocks IL-4 and IL-13 is also being developed as a treatment for eosinophilic asthma. Dr. Beck was first author of a report on a series of four phase II randomized trials of dupilumab for moderate to severe atopic dermatitis in adults. The publication caused a stir, with dupilumab-treated patients showing marked and rapid improvement to a degree previously unseen in the treatment of this disease (N Engl J Med. 2014;371[2]:130-9).

In the 12-week study, for example, 85% of dupilumab-treated patients achieved at least a 50% improvement in the Eczema Area and Severity Index (EASI) score, compared with 35% of placebo-treated controls, with a significant between-group difference seen in the first week. Maximum improvement – a 75%-80% reduction in EASI scores – was noted at 6-8 weeks. Forty percent of dupilumab-treated patients achieved clear or near-clear skin by investigator’s global assessment, compared with just 7% of controls.

Itching decreased markedly beginning in the first week, too. The investigational agent’s side effect profile was similar to placebo. Phase III clinical trials in atopic dermatitis are ongoing.

A study by other investigators found that dupilumab resulted in rapid improvement in the molecular signature of atopic dermatitis in skin biopsy specimens (J Allergy Clin Immunol. 2014 Dec;134[6]:1293-300). The observed changes in gene expression suggest that dupilumab might have a beneficial effect on the dysfunctional skin barrier that is a hallmark of atopic dermatitis. Further studies are now being planned to take a closer look at that possibility.

JAK inhibitors: “We’re all really excited about this approach because dogs, too, get allergic dermatitis, and in 2013 a JAK 1 and 3 inhibitor [oclacitinib, Apoquel] was approved as a veterinary medicine therapy. It has resulted in dramatic improvement in itch within 1 week of administration, as well as significant improvement in the dermatitis,” Dr. Beck said.

Three JAK inhibitors are now in phase II clinical trials for atopic dermatitis in humans: the JAK 1 and 3 inhibitor tofacitinib (Xeljanz), both as a topical ointment and the familiar oral formulation; baricitinib, an oral JAK 1 and 2 inhibitor; and an agent known for now as PF-04965842, which is an oral inhibitor specifically of JAK 1.

“JAK inhibitors have been quite effective in treating a number of other inflammatory conditions, as well as cancers. I think they will have a role in the treatment of atopic dermatitis. The biggest concerns will be the off-target effects,” she predicted.

Anti-IgE agents: Omalizumab (Xolair), a humanized monoclonal antibody that binds to IgE, has gotten mixed reviews as an investigational treatment for atopic dermatitis. The best study to date, a randomized, single-center, placebo-controlled, double-blind, 16-week clinical trial, found that omalizumab depleted IgE but didn’t improve the clinical course of atopic dermatitis (J Dtsch Dermatol Ges. 2010 Dec;8[12]:990-8). Nonetheless, a phase II trial of omalizumab is ongoing. Plus, ligelizumab, an anti-IgE monoclonal antibody with a higher affinity for IgE than omalizumab, is also in a phase II trial for adult atopic dermatitis.

“Anti-IgE therapy, I think, is still not dead in atopic dermatitis. I look forward to seeing whether omalizumab will work in unique subsets of patients, or whether a more potent anti-IgE molecule will be more beneficial,” Dr. Beck commented.

As exciting as the prospects are for these investigational agents, there also have been several recent important advances in the prevention of atopic dermatitis, she continued. Investigators led by Dr. Alan D. Irvine of Trinity College, Dublin, noninvasively measured transepidermal water loss in early infancy in more than 1,900 Irish 2-day-old infants and found that those in the 75th percentile for this early marker of skin barrier dysfunction were at 3.1-fold increased risk for diagnosis of atopic dermatitis by age 2 years (J Allergy Clin Immunol. 2016 Apr;137[4]:1111-6). This new-found ability to identify at-risk infants will be extremely helpful in designing atopic dermatitis prevention studies, according to Dr. Beck.

The other advance in prevention was provided via a randomized trial by Dr. Eric L. Simpson of Oregon Health and Science University, Portland, and his coinvestigators. They randomized a group of infants at high risk for atopic dermatitis to daily application of any of five OTC skin moisturizers or a no-moisturizer control group from 2 weeks through 6 months of age. The study hypothesis was that the moisturizers would help reverse the skin barrier abnormalities that play a key role in atopic dermatitis. The hypothesis was borne out by the finding that there was at least a 50% reduction in physician-diagnosed atopic dermatitis by age 6 months in the daily moisturizer group (J Allergy Clin Immunol. 2014 Oct;134[4]:818-23).

Dr. Beck concluded by describing a likely near-term atopic dermatitis prevention and management scenario: High-risk infants will be identified on the basis of noninvasive assessment of epithelial features, such as transepidermal water loss or the presence of high levels of thymic stromal lymphopoietin on the skin surface. Encouragement of daily moisturizing for these high-risk infants will prevent some of them from going on to develop eczema.

For those who do get eczema, dilute bleach baths will help in restoring normal skin barrier function, as was confirmed in an in-press study by Dr. Beck and her coinvestigators, who found that 46% of a group of adults with atopic dermatitis experienced at least a 50% improvement in EASI scores, a big improvement in itch, and reduced transepidermal water loss after 12 weeks of the bleach baths. As other investigators have reported, the bleach baths were very well tolerated and safe.

Dr. Beck reported serving as a consultant to eight pharmaceutical companies with an interest in developing new treatments for atopic dermatitis.

bjancin@frontlinemedcom.com

Although the classic Norwood palliation for infants with hypoplastic left heart syndrome (HLHS) has been well established, the procedure has had its drawbacks, namely the need for cardiopulmonary bypass with hypothermia and a because it rules out biventricular correction months later. A hybrid procedure avoids the need for bypass and accommodates short-term biventricular correction, but it has lacked strong evidence.

Researchers from Justus-Liebig University Giessen, Germany, reported on 182 patients with HLHS who had the three-stage Giessen hybrid procedure, noting 10-year survival of almost 80% with almost a third of patients requiring no artery intervention in that time (J Thorac Cardiovasc Surg. 2016 April;151:1112-23).

“In view of the early results and long-term outcome after Giessen hybrid palliation, the hybrid approach has become a reasonable alternative to the conventional strategy to treat neonates with HLHS and variants,” wrote Dr. Can Yerebakan and colleagues. “Further refinements are warranted to decrease patient morbidity.”

The Giessen hybrid procedure uses a technique to control pulmonary blood flow that is different from the Norwood procedure. The hybrid approach involves stenting of the arterial duct or prostaglandin therapy to maintain systemic perfusion combined with off-pump bilateral banding of the pulmonary arteries (bPAB) in the neonatal period. The Giessen hybrid operation defers the Norwood-type palliation using cardiopulmonary bypass that involves an aortic arch reconstruction, including a superior cavopulmonary connection or a biventricular correction, if indicated, until the infant is 4-8 months of age.

“In recent years, hybrid treatment has moved from a myth to an alternative modality in a growing number of institutions globally,” Dr. Yerebakan and colleagues said. The hybrid procedure has been used in high-risk patients. One report claimed higher morbidity in the hybrid procedure due to bPAB (Ann Thorac Surg. 2013;96:1382-8). Another study raised concerns about an adequate pulmonary artery rehabilitation at the time of the Fontan operation, the third stage in the hybrid strategy (J Thorac Cardiovasc Surg. 2014;147:706-12).

But with the hybrid approach, patients retain the potential to receive a biventricular correction up to 8 months later without compromising survival, “postponing an immediate definitive decision in the newborn period in comparison with the classic Norwood palliation,” Dr. Yerebakan and coauthors noted.

The doctors at the Pediatric Heart Center Giessen treat all types and variants of HLHS with the modified Giessen hybrid strategy. Between 1998 and 2015, 182 patients with HLHS had the Giessen hybrid stage I operation, including 126 patients who received univentricular palliation or a heart transplant. The median age of stage I recipients was 6 days, and median weight 3.2 kg. The stage II operation was performed at 4.5 months, with a range of 2.9 to 39.5 months, and Fontan completion was established at 33.7 months, with a range of 21 to 108 months.

Median follow-up after the stage I procedure was 4.6 years, and the death rate was 2.5%. After stage II, mortality was 4.9%; no deaths were reported after Fontan completion. Body weight less than 2.5 kg and aortic atresia had no significant effect on survival. Mortality rates were 8.9% between stages I and II and 5.3% between stage II and Fontan completion. “Cumulative interstage mortality was 14.2%,” Dr. Yerebakan and colleagues noted. “At 10 years, the probability of survival is 77.8%.”

Also at 10 years, 32.2% of patients were free from further pulmonary artery intervention, and 16.7% needed aortic arch reconstruction. Two patients required reoperations for aortic arch reconstruction.

Dr. Yerebakan and colleagues suggested several steps to improve outcomes with the hybrid approach: “intense collaboration” with anesthesiology and pediatric cardiology during and after the procedure to risk stratify individual patients; implementation of standards for management of all stages, including out-of-hospital care, in all departments that participate in a case; and liberalized indications for use of MRI before the stage II and Fontan completion.

Among the limitations of the study the authors noted were its retrospective nature and a median follow-up of only 5 years when the center has some cases with up to 15 years of follow-up. But Dr. Yerebakan and coauthors said they could not determine if the patients benefit from the hybrid treatment in the long-term.

The researchers had no disclosures.

Although the classic Norwood palliation for infants with hypoplastic left heart syndrome (HLHS) has been well established, the procedure has had its drawbacks, namely the need for cardiopulmonary bypass with hypothermia and a because it rules out biventricular correction months later. A hybrid procedure avoids the need for bypass and accommodates short-term biventricular correction, but it has lacked strong evidence.

Researchers from Justus-Liebig University Giessen, Germany, reported on 182 patients with HLHS who had the three-stage Giessen hybrid procedure, noting 10-year survival of almost 80% with almost a third of patients requiring no artery intervention in that time (J Thorac Cardiovasc Surg. 2016 April;151:1112-23).

“In view of the early results and long-term outcome after Giessen hybrid palliation, the hybrid approach has become a reasonable alternative to the conventional strategy to treat neonates with HLHS and variants,” wrote Dr. Can Yerebakan and colleagues. “Further refinements are warranted to decrease patient morbidity.”

The Giessen hybrid procedure uses a technique to control pulmonary blood flow that is different from the Norwood procedure. The hybrid approach involves stenting of the arterial duct or prostaglandin therapy to maintain systemic perfusion combined with off-pump bilateral banding of the pulmonary arteries (bPAB) in the neonatal period. The Giessen hybrid operation defers the Norwood-type palliation using cardiopulmonary bypass that involves an aortic arch reconstruction, including a superior cavopulmonary connection or a biventricular correction, if indicated, until the infant is 4-8 months of age.

“In recent years, hybrid treatment has moved from a myth to an alternative modality in a growing number of institutions globally,” Dr. Yerebakan and colleagues said. The hybrid procedure has been used in high-risk patients. One report claimed higher morbidity in the hybrid procedure due to bPAB (Ann Thorac Surg. 2013;96:1382-8). Another study raised concerns about an adequate pulmonary artery rehabilitation at the time of the Fontan operation, the third stage in the hybrid strategy (J Thorac Cardiovasc Surg. 2014;147:706-12).

But with the hybrid approach, patients retain the potential to receive a biventricular correction up to 8 months later without compromising survival, “postponing an immediate definitive decision in the newborn period in comparison with the classic Norwood palliation,” Dr. Yerebakan and coauthors noted.

The doctors at the Pediatric Heart Center Giessen treat all types and variants of HLHS with the modified Giessen hybrid strategy. Between 1998 and 2015, 182 patients with HLHS had the Giessen hybrid stage I operation, including 126 patients who received univentricular palliation or a heart transplant. The median age of stage I recipients was 6 days, and median weight 3.2 kg. The stage II operation was performed at 4.5 months, with a range of 2.9 to 39.5 months, and Fontan completion was established at 33.7 months, with a range of 21 to 108 months.

Median follow-up after the stage I procedure was 4.6 years, and the death rate was 2.5%. After stage II, mortality was 4.9%; no deaths were reported after Fontan completion. Body weight less than 2.5 kg and aortic atresia had no significant effect on survival. Mortality rates were 8.9% between stages I and II and 5.3% between stage II and Fontan completion. “Cumulative interstage mortality was 14.2%,” Dr. Yerebakan and colleagues noted. “At 10 years, the probability of survival is 77.8%.”

Also at 10 years, 32.2% of patients were free from further pulmonary artery intervention, and 16.7% needed aortic arch reconstruction. Two patients required reoperations for aortic arch reconstruction.

Dr. Yerebakan and colleagues suggested several steps to improve outcomes with the hybrid approach: “intense collaboration” with anesthesiology and pediatric cardiology during and after the procedure to risk stratify individual patients; implementation of standards for management of all stages, including out-of-hospital care, in all departments that participate in a case; and liberalized indications for use of MRI before the stage II and Fontan completion.

Among the limitations of the study the authors noted were its retrospective nature and a median follow-up of only 5 years when the center has some cases with up to 15 years of follow-up. But Dr. Yerebakan and coauthors said they could not determine if the patients benefit from the hybrid treatment in the long-term.

The researchers had no disclosures.

Although the classic Norwood palliation for infants with hypoplastic left heart syndrome (HLHS) has been well established, the procedure has had its drawbacks, namely the need for cardiopulmonary bypass with hypothermia and a because it rules out biventricular correction months later. A hybrid procedure avoids the need for bypass and accommodates short-term biventricular correction, but it has lacked strong evidence.

Researchers from Justus-Liebig University Giessen, Germany, reported on 182 patients with HLHS who had the three-stage Giessen hybrid procedure, noting 10-year survival of almost 80% with almost a third of patients requiring no artery intervention in that time (J Thorac Cardiovasc Surg. 2016 April;151:1112-23).

“In view of the early results and long-term outcome after Giessen hybrid palliation, the hybrid approach has become a reasonable alternative to the conventional strategy to treat neonates with HLHS and variants,” wrote Dr. Can Yerebakan and colleagues. “Further refinements are warranted to decrease patient morbidity.”

The Giessen hybrid procedure uses a technique to control pulmonary blood flow that is different from the Norwood procedure. The hybrid approach involves stenting of the arterial duct or prostaglandin therapy to maintain systemic perfusion combined with off-pump bilateral banding of the pulmonary arteries (bPAB) in the neonatal period. The Giessen hybrid operation defers the Norwood-type palliation using cardiopulmonary bypass that involves an aortic arch reconstruction, including a superior cavopulmonary connection or a biventricular correction, if indicated, until the infant is 4-8 months of age.

“In recent years, hybrid treatment has moved from a myth to an alternative modality in a growing number of institutions globally,” Dr. Yerebakan and colleagues said. The hybrid procedure has been used in high-risk patients. One report claimed higher morbidity in the hybrid procedure due to bPAB (Ann Thorac Surg. 2013;96:1382-8). Another study raised concerns about an adequate pulmonary artery rehabilitation at the time of the Fontan operation, the third stage in the hybrid strategy (J Thorac Cardiovasc Surg. 2014;147:706-12).

But with the hybrid approach, patients retain the potential to receive a biventricular correction up to 8 months later without compromising survival, “postponing an immediate definitive decision in the newborn period in comparison with the classic Norwood palliation,” Dr. Yerebakan and coauthors noted.

The doctors at the Pediatric Heart Center Giessen treat all types and variants of HLHS with the modified Giessen hybrid strategy. Between 1998 and 2015, 182 patients with HLHS had the Giessen hybrid stage I operation, including 126 patients who received univentricular palliation or a heart transplant. The median age of stage I recipients was 6 days, and median weight 3.2 kg. The stage II operation was performed at 4.5 months, with a range of 2.9 to 39.5 months, and Fontan completion was established at 33.7 months, with a range of 21 to 108 months.

Median follow-up after the stage I procedure was 4.6 years, and the death rate was 2.5%. After stage II, mortality was 4.9%; no deaths were reported after Fontan completion. Body weight less than 2.5 kg and aortic atresia had no significant effect on survival. Mortality rates were 8.9% between stages I and II and 5.3% between stage II and Fontan completion. “Cumulative interstage mortality was 14.2%,” Dr. Yerebakan and colleagues noted. “At 10 years, the probability of survival is 77.8%.”

Also at 10 years, 32.2% of patients were free from further pulmonary artery intervention, and 16.7% needed aortic arch reconstruction. Two patients required reoperations for aortic arch reconstruction.

Dr. Yerebakan and colleagues suggested several steps to improve outcomes with the hybrid approach: “intense collaboration” with anesthesiology and pediatric cardiology during and after the procedure to risk stratify individual patients; implementation of standards for management of all stages, including out-of-hospital care, in all departments that participate in a case; and liberalized indications for use of MRI before the stage II and Fontan completion.

Among the limitations of the study the authors noted were its retrospective nature and a median follow-up of only 5 years when the center has some cases with up to 15 years of follow-up. But Dr. Yerebakan and coauthors said they could not determine if the patients benefit from the hybrid treatment in the long-term.

The researchers had no disclosures.

A few weeks ago, Marilyn and I were left in charge of two of our grandchildren, 8 and 10 years old. The morning was overcast and drizzly, eliminating their first choice of going to the college athletic fields to practice their lacrosse skills. A game of Monopoly seemed like a good idea until it became obvious that someone was going to win and that another someone who doesn’t handle defeat very well was going to lose. So off we went to the bowling alley. As we pulled into the sparsely occupied parking lot, the ever-observant 8-year-old noted that almost all of the vehicles were vans.

As we checked in to rent our shoes, the explanation for the vans became clear. It turns out that on Thursday mornings, the bowling alley is the place to be if you are an adult with a mental disability in Brunswick, Maine.

Our grandchildren had a wonderful hour of bowling surrounded by the cacophony created by the several dozen adults with whom we were sharing the lanes. As my wife and I revisited our morning adventure that evening, we recalled how comfortable our grandchildren had been in the midst of a scenario that had the chaotic feel of a Hieronymus Bosch painting.

The explanation for their lack of discomfort lies in the fact that they have grown up in a time and in a town in which the individuals with chromosomal anomalies and birth injury are accepted and cared for in the community and not hidden away in an institution. Our grandchildren’s parents were born as this sea change was just beginning. In fact, when my son was born, I was moonlighting as the night emergency physician at an institution that housed a few hundred of these individuals, many of whom had disabilities similar to those of the folks with whom we had shared the bowling alley. It closed a few years later. And, by the time my son and his sisters entered middle school, they had become accustomed to having classmates with mental disabilities.

The next step in the evolution came when the children who had been “mainstreamed” grew too old for high school and began transitioning to the handful of small group homes that sprang up around the community. It was not always a smooth process and would not have happened without tireless pressure from their parents. Even today, funding and staffing problems continue. Despite initial concerns that some neighborhoods might resist the introduction of a group home, acceptance has not been a problem.

It has almost been a win-win situation. Our citizens with mental disabilities have a far richer life than they would have had in even the most progressive institution. And the rest of us have benefited by learning tolerance from having our challenged family members close by.

However, the transition from institutionalization to community-based support has not been without its downside, particularly for a small town like Brunswick, Maine. Federal and state mandates now place on the shoulders of the school a significant financial burden for the special services required by children with mental disabilities. Small communities with only a few students with disabilities can’t benefit from the economies of scale that allow larger school systems to staff their programs more efficiently and provide more specialized services. Smaller school districts can sometimes pool their resources. But if this solution necessitates transporting the students with mental disabilities out of their own school district to a central location, it runs the risk of robbing the other students, like my grandchildren, of an enriching experience that I wouldn’t want to see them lose.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including “How to Say No to Your Toddler.”

A few weeks ago, Marilyn and I were left in charge of two of our grandchildren, 8 and 10 years old. The morning was overcast and drizzly, eliminating their first choice of going to the college athletic fields to practice their lacrosse skills. A game of Monopoly seemed like a good idea until it became obvious that someone was going to win and that another someone who doesn’t handle defeat very well was going to lose. So off we went to the bowling alley. As we pulled into the sparsely occupied parking lot, the ever-observant 8-year-old noted that almost all of the vehicles were vans.

As we checked in to rent our shoes, the explanation for the vans became clear. It turns out that on Thursday mornings, the bowling alley is the place to be if you are an adult with a mental disability in Brunswick, Maine.

Our grandchildren had a wonderful hour of bowling surrounded by the cacophony created by the several dozen adults with whom we were sharing the lanes. As my wife and I revisited our morning adventure that evening, we recalled how comfortable our grandchildren had been in the midst of a scenario that had the chaotic feel of a Hieronymus Bosch painting.

The explanation for their lack of discomfort lies in the fact that they have grown up in a time and in a town in which the individuals with chromosomal anomalies and birth injury are accepted and cared for in the community and not hidden away in an institution. Our grandchildren’s parents were born as this sea change was just beginning. In fact, when my son was born, I was moonlighting as the night emergency physician at an institution that housed a few hundred of these individuals, many of whom had disabilities similar to those of the folks with whom we had shared the bowling alley. It closed a few years later. And, by the time my son and his sisters entered middle school, they had become accustomed to having classmates with mental disabilities.

The next step in the evolution came when the children who had been “mainstreamed” grew too old for high school and began transitioning to the handful of small group homes that sprang up around the community. It was not always a smooth process and would not have happened without tireless pressure from their parents. Even today, funding and staffing problems continue. Despite initial concerns that some neighborhoods might resist the introduction of a group home, acceptance has not been a problem.

It has almost been a win-win situation. Our citizens with mental disabilities have a far richer life than they would have had in even the most progressive institution. And the rest of us have benefited by learning tolerance from having our challenged family members close by.

However, the transition from institutionalization to community-based support has not been without its downside, particularly for a small town like Brunswick, Maine. Federal and state mandates now place on the shoulders of the school a significant financial burden for the special services required by children with mental disabilities. Small communities with only a few students with disabilities can’t benefit from the economies of scale that allow larger school systems to staff their programs more efficiently and provide more specialized services. Smaller school districts can sometimes pool their resources. But if this solution necessitates transporting the students with mental disabilities out of their own school district to a central location, it runs the risk of robbing the other students, like my grandchildren, of an enriching experience that I wouldn’t want to see them lose.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including “How to Say No to Your Toddler.”

A few weeks ago, Marilyn and I were left in charge of two of our grandchildren, 8 and 10 years old. The morning was overcast and drizzly, eliminating their first choice of going to the college athletic fields to practice their lacrosse skills. A game of Monopoly seemed like a good idea until it became obvious that someone was going to win and that another someone who doesn’t handle defeat very well was going to lose. So off we went to the bowling alley. As we pulled into the sparsely occupied parking lot, the ever-observant 8-year-old noted that almost all of the vehicles were vans.

As we checked in to rent our shoes, the explanation for the vans became clear. It turns out that on Thursday mornings, the bowling alley is the place to be if you are an adult with a mental disability in Brunswick, Maine.

Our grandchildren had a wonderful hour of bowling surrounded by the cacophony created by the several dozen adults with whom we were sharing the lanes. As my wife and I revisited our morning adventure that evening, we recalled how comfortable our grandchildren had been in the midst of a scenario that had the chaotic feel of a Hieronymus Bosch painting.

The explanation for their lack of discomfort lies in the fact that they have grown up in a time and in a town in which the individuals with chromosomal anomalies and birth injury are accepted and cared for in the community and not hidden away in an institution. Our grandchildren’s parents were born as this sea change was just beginning. In fact, when my son was born, I was moonlighting as the night emergency physician at an institution that housed a few hundred of these individuals, many of whom had disabilities similar to those of the folks with whom we had shared the bowling alley. It closed a few years later. And, by the time my son and his sisters entered middle school, they had become accustomed to having classmates with mental disabilities.

The next step in the evolution came when the children who had been “mainstreamed” grew too old for high school and began transitioning to the handful of small group homes that sprang up around the community. It was not always a smooth process and would not have happened without tireless pressure from their parents. Even today, funding and staffing problems continue. Despite initial concerns that some neighborhoods might resist the introduction of a group home, acceptance has not been a problem.

It has almost been a win-win situation. Our citizens with mental disabilities have a far richer life than they would have had in even the most progressive institution. And the rest of us have benefited by learning tolerance from having our challenged family members close by.

However, the transition from institutionalization to community-based support has not been without its downside, particularly for a small town like Brunswick, Maine. Federal and state mandates now place on the shoulders of the school a significant financial burden for the special services required by children with mental disabilities. Small communities with only a few students with disabilities can’t benefit from the economies of scale that allow larger school systems to staff their programs more efficiently and provide more specialized services. Smaller school districts can sometimes pool their resources. But if this solution necessitates transporting the students with mental disabilities out of their own school district to a central location, it runs the risk of robbing the other students, like my grandchildren, of an enriching experience that I wouldn’t want to see them lose.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including “How to Say No to Your Toddler.”

Lisa Diller, MD

Photo from Dana-Farber/

Boston Children’s Cancer

and Blood Disorders Center

Young adult survivors of childhood cancer tend to have inferior health-related quality of life (HRQOL) when compared to the general population, according to research published in the Journal of the National Cancer Institute.

Childhood cancer survivors (CCSs) ages 18 to 29 reported overall HRQOL similar to that of people from the general population who were in their 40s.

However, CCSs fared better if they did not have chronic health conditions.

“Our findings indicate survivors’ accelerated aging and also help us understand the health-related risks associated with having had cancer as a child,” said study author Lisa Diller, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School in Boston, Massachusetts.

“What’s encouraging is that the lower quality of life scores are associated with chronic disease after treatment, not with a history of pediatric cancer itself. If we can prevent treatment-related conditions by changes in the therapy we use for the cancer, then childhood cancer will become an acute, rather than a chronic, illness.”

Dr Diller and her colleagues used information from the Childhood Cancer Survivor Study to compare CCSs (n=7105) and their siblings (n=372) and information from the Medical Expenditures Panel Survey to make comparisons to the general population (n=12,803).

The researchers estimated health utility, a summary measure of quality of life, in these subjects using the Short Form-6D (SF-6D). A score of “1” indicated perfect health, and a score of “0” indicated death.

Results showed that CCSs had significantly lower SF-6D scores than the general population. The mean scores were 0.77 and 0.81, respectively (P<0.001).

But there were no clinically meaningful differences between the CCSs’ siblings and the general population. Their mean SF-6D scores were 0.80 and 0.81, respectively.

Young adult CCSs ages 18 to 29 had a mean score of 0.78, which was roughly equivalent to that reported for 40-to-49-year-old adults in the general population.

However, the presence or absence of chronic health conditions played a role in HRQOL. CCSs who reported no chronic conditions had SF-6D scores similar to the general population, with a mean score of 0.81.

But CCSs with chronic conditions had scores that matched the scores of chronically ill members of the general population. CCSs with 2 chronic conditions had a mean score of 0.77. Those with 3 or more disabling, severe, or life-threatening conditions had a mean score of 0.70.

“By enabling comparisons to the general population, our findings provide context to better understand how the cancer experience may influence the long-term well-being of survivors,” said study author Jennifer Yeh, PhD, of the Harvard T.H. Chan School of Public Health in Boston.

“This is another way to understand the health challenges survivors face and where to focus efforts to improve the long-term health and quality of life of survivors.”

Lisa Diller, MD

Photo from Dana-Farber/

Boston Children’s Cancer

and Blood Disorders Center

Young adult survivors of childhood cancer tend to have inferior health-related quality of life (HRQOL) when compared to the general population, according to research published in the Journal of the National Cancer Institute.

Childhood cancer survivors (CCSs) ages 18 to 29 reported overall HRQOL similar to that of people from the general population who were in their 40s.

However, CCSs fared better if they did not have chronic health conditions.

“Our findings indicate survivors’ accelerated aging and also help us understand the health-related risks associated with having had cancer as a child,” said study author Lisa Diller, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School in Boston, Massachusetts.

“What’s encouraging is that the lower quality of life scores are associated with chronic disease after treatment, not with a history of pediatric cancer itself. If we can prevent treatment-related conditions by changes in the therapy we use for the cancer, then childhood cancer will become an acute, rather than a chronic, illness.”

Dr Diller and her colleagues used information from the Childhood Cancer Survivor Study to compare CCSs (n=7105) and their siblings (n=372) and information from the Medical Expenditures Panel Survey to make comparisons to the general population (n=12,803).

The researchers estimated health utility, a summary measure of quality of life, in these subjects using the Short Form-6D (SF-6D). A score of “1” indicated perfect health, and a score of “0” indicated death.

Results showed that CCSs had significantly lower SF-6D scores than the general population. The mean scores were 0.77 and 0.81, respectively (P<0.001).

But there were no clinically meaningful differences between the CCSs’ siblings and the general population. Their mean SF-6D scores were 0.80 and 0.81, respectively.

Young adult CCSs ages 18 to 29 had a mean score of 0.78, which was roughly equivalent to that reported for 40-to-49-year-old adults in the general population.

However, the presence or absence of chronic health conditions played a role in HRQOL. CCSs who reported no chronic conditions had SF-6D scores similar to the general population, with a mean score of 0.81.

But CCSs with chronic conditions had scores that matched the scores of chronically ill members of the general population. CCSs with 2 chronic conditions had a mean score of 0.77. Those with 3 or more disabling, severe, or life-threatening conditions had a mean score of 0.70.

“By enabling comparisons to the general population, our findings provide context to better understand how the cancer experience may influence the long-term well-being of survivors,” said study author Jennifer Yeh, PhD, of the Harvard T.H. Chan School of Public Health in Boston.

“This is another way to understand the health challenges survivors face and where to focus efforts to improve the long-term health and quality of life of survivors.”

Lisa Diller, MD

Photo from Dana-Farber/

Boston Children’s Cancer

and Blood Disorders Center

Young adult survivors of childhood cancer tend to have inferior health-related quality of life (HRQOL) when compared to the general population, according to research published in the Journal of the National Cancer Institute.

Childhood cancer survivors (CCSs) ages 18 to 29 reported overall HRQOL similar to that of people from the general population who were in their 40s.

However, CCSs fared better if they did not have chronic health conditions.

“Our findings indicate survivors’ accelerated aging and also help us understand the health-related risks associated with having had cancer as a child,” said study author Lisa Diller, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School in Boston, Massachusetts.

“What’s encouraging is that the lower quality of life scores are associated with chronic disease after treatment, not with a history of pediatric cancer itself. If we can prevent treatment-related conditions by changes in the therapy we use for the cancer, then childhood cancer will become an acute, rather than a chronic, illness.”

Dr Diller and her colleagues used information from the Childhood Cancer Survivor Study to compare CCSs (n=7105) and their siblings (n=372) and information from the Medical Expenditures Panel Survey to make comparisons to the general population (n=12,803).

The researchers estimated health utility, a summary measure of quality of life, in these subjects using the Short Form-6D (SF-6D). A score of “1” indicated perfect health, and a score of “0” indicated death.

Results showed that CCSs had significantly lower SF-6D scores than the general population. The mean scores were 0.77 and 0.81, respectively (P<0.001).

But there were no clinically meaningful differences between the CCSs’ siblings and the general population. Their mean SF-6D scores were 0.80 and 0.81, respectively.

Young adult CCSs ages 18 to 29 had a mean score of 0.78, which was roughly equivalent to that reported for 40-to-49-year-old adults in the general population.

However, the presence or absence of chronic health conditions played a role in HRQOL. CCSs who reported no chronic conditions had SF-6D scores similar to the general population, with a mean score of 0.81.

But CCSs with chronic conditions had scores that matched the scores of chronically ill members of the general population. CCSs with 2 chronic conditions had a mean score of 0.77. Those with 3 or more disabling, severe, or life-threatening conditions had a mean score of 0.70.

“By enabling comparisons to the general population, our findings provide context to better understand how the cancer experience may influence the long-term well-being of survivors,” said study author Jennifer Yeh, PhD, of the Harvard T.H. Chan School of Public Health in Boston.

“This is another way to understand the health challenges survivors face and where to focus efforts to improve the long-term health and quality of life of survivors.”

Brian Sorrentino, MD

Photo courtesy of St. Jude

Children’s Research Hospital

Lentiviral gene therapy with reduced-intensity conditioning can provide long-term benefits for older patients with X-linked severe combined immunodeficiency (SCID-X1), according to a small study.

All 5 patients who received this therapy exhibited selective expansion of gene-marked B, T, and natural killer (NK) cells.

In 2 of the older patients, the treatment restored normal immune function, an effect that lasted 2 and 3 years, respectively.

“This study demonstrates that lentivirus gene therapy, when combined with busulfan conditioning, can rebuild the immune system and lead to broad immunity in young adults with this devastating disorder,” said Brian Sorrentino, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Sorrentino and his colleagues described this research in Science Translational Medicine.

The researchers explained that SCID-X1 is a profound deficiency of T, B, and NK cell immunity caused by mutations in IL2RG encoding the common chain (γc) of several interleukin receptors. And gammaretroviral gene therapy given without conditioning can restore T-cell immunity in young children with SCID-X1 but fails in older patients.

With this in mind, the team developed a lentiviral vector γc transduced autologous hematopoietic stem cell (HSC) gene therapy and tested it with nonmyeloablative busulfan conditioning in 5 SCID-X1 patients.

The patients were 7 to 23 years old. They all had chronic viral infections and other health problems related to SCID-X1, despite having received 1 or more haploidentical HSC transplants.

More than 2 years after undergoing gene therapy, the first 2 patients (ages 22 and 23) were producing a greater percentage of T, B, and NK cells with the corrected gene. The therapy had also restored antibody production in response to vaccination.

Furthermore, the patients’ health improved as their chronic viral infections resolved, and they put on weight as their protein absorption improved. One patient’s disfiguring warts were eased, and both patients ended life-long immune globulin therapy.

However, one of these patients died from pre-existing lung damage more than 2 years after receiving gene therapy.

Like the 2 older patients, the 3 younger patients (ages 7, 10, and 15) began producing a greater percentage of T, B, and NK cells with the corrected gene after therapy. But the younger patients have only been followed for several months.

The researchers said the safety results in this study were reassuring. There were no adverse events associated with the gene therapy and no indication of possible precancer cell proliferation.

As expected, patients experienced busulfan-related neutropenia and thrombocytopenia but recovered without any intervention. And 3 patients developed febrile neutropenia that responded to empiric antimicrobial therapy.

“While additional clinical experience and follow-up is needed, these promising results suggest gene therapy should be considered as an early treatment for patients in order to minimize or prevent the life-threatening organ damage that occurs when bone marrow transplant therapy fails to provide a sufficient immune response,” Dr Sorrentino said.

To that end, St. Jude has opened a gene therapy trial using the same lentiviral vector and busulfan conditioning for newly identified infants with SCID-X1 who lack a genetically matched sibling HSC donor.

“Based on the safety and health benefits for older patients reported in this study, we hope this novel gene therapy will help improve immune functioning and transform the lives of younger patients with this devastating disease,” Dr Sorrentino said.

Brian Sorrentino, MD

Photo courtesy of St. Jude

Children’s Research Hospital

Lentiviral gene therapy with reduced-intensity conditioning can provide long-term benefits for older patients with X-linked severe combined immunodeficiency (SCID-X1), according to a small study.

All 5 patients who received this therapy exhibited selective expansion of gene-marked B, T, and natural killer (NK) cells.

In 2 of the older patients, the treatment restored normal immune function, an effect that lasted 2 and 3 years, respectively.

“This study demonstrates that lentivirus gene therapy, when combined with busulfan conditioning, can rebuild the immune system and lead to broad immunity in young adults with this devastating disorder,” said Brian Sorrentino, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Sorrentino and his colleagues described this research in Science Translational Medicine.

The researchers explained that SCID-X1 is a profound deficiency of T, B, and NK cell immunity caused by mutations in IL2RG encoding the common chain (γc) of several interleukin receptors. And gammaretroviral gene therapy given without conditioning can restore T-cell immunity in young children with SCID-X1 but fails in older patients.

With this in mind, the team developed a lentiviral vector γc transduced autologous hematopoietic stem cell (HSC) gene therapy and tested it with nonmyeloablative busulfan conditioning in 5 SCID-X1 patients.

The patients were 7 to 23 years old. They all had chronic viral infections and other health problems related to SCID-X1, despite having received 1 or more haploidentical HSC transplants.

More than 2 years after undergoing gene therapy, the first 2 patients (ages 22 and 23) were producing a greater percentage of T, B, and NK cells with the corrected gene. The therapy had also restored antibody production in response to vaccination.

Furthermore, the patients’ health improved as their chronic viral infections resolved, and they put on weight as their protein absorption improved. One patient’s disfiguring warts were eased, and both patients ended life-long immune globulin therapy.

However, one of these patients died from pre-existing lung damage more than 2 years after receiving gene therapy.

Like the 2 older patients, the 3 younger patients (ages 7, 10, and 15) began producing a greater percentage of T, B, and NK cells with the corrected gene after therapy. But the younger patients have only been followed for several months.

The researchers said the safety results in this study were reassuring. There were no adverse events associated with the gene therapy and no indication of possible precancer cell proliferation.

As expected, patients experienced busulfan-related neutropenia and thrombocytopenia but recovered without any intervention. And 3 patients developed febrile neutropenia that responded to empiric antimicrobial therapy.

“While additional clinical experience and follow-up is needed, these promising results suggest gene therapy should be considered as an early treatment for patients in order to minimize or prevent the life-threatening organ damage that occurs when bone marrow transplant therapy fails to provide a sufficient immune response,” Dr Sorrentino said.

To that end, St. Jude has opened a gene therapy trial using the same lentiviral vector and busulfan conditioning for newly identified infants with SCID-X1 who lack a genetically matched sibling HSC donor.

“Based on the safety and health benefits for older patients reported in this study, we hope this novel gene therapy will help improve immune functioning and transform the lives of younger patients with this devastating disease,” Dr Sorrentino said.

Brian Sorrentino, MD

Photo courtesy of St. Jude

Children’s Research Hospital

Lentiviral gene therapy with reduced-intensity conditioning can provide long-term benefits for older patients with X-linked severe combined immunodeficiency (SCID-X1), according to a small study.

All 5 patients who received this therapy exhibited selective expansion of gene-marked B, T, and natural killer (NK) cells.

In 2 of the older patients, the treatment restored normal immune function, an effect that lasted 2 and 3 years, respectively.

“This study demonstrates that lentivirus gene therapy, when combined with busulfan conditioning, can rebuild the immune system and lead to broad immunity in young adults with this devastating disorder,” said Brian Sorrentino, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Sorrentino and his colleagues described this research in Science Translational Medicine.

The researchers explained that SCID-X1 is a profound deficiency of T, B, and NK cell immunity caused by mutations in IL2RG encoding the common chain (γc) of several interleukin receptors. And gammaretroviral gene therapy given without conditioning can restore T-cell immunity in young children with SCID-X1 but fails in older patients.

With this in mind, the team developed a lentiviral vector γc transduced autologous hematopoietic stem cell (HSC) gene therapy and tested it with nonmyeloablative busulfan conditioning in 5 SCID-X1 patients.

The patients were 7 to 23 years old. They all had chronic viral infections and other health problems related to SCID-X1, despite having received 1 or more haploidentical HSC transplants.

More than 2 years after undergoing gene therapy, the first 2 patients (ages 22 and 23) were producing a greater percentage of T, B, and NK cells with the corrected gene. The therapy had also restored antibody production in response to vaccination.

Furthermore, the patients’ health improved as their chronic viral infections resolved, and they put on weight as their protein absorption improved. One patient’s disfiguring warts were eased, and both patients ended life-long immune globulin therapy.

However, one of these patients died from pre-existing lung damage more than 2 years after receiving gene therapy.

Like the 2 older patients, the 3 younger patients (ages 7, 10, and 15) began producing a greater percentage of T, B, and NK cells with the corrected gene after therapy. But the younger patients have only been followed for several months.

The researchers said the safety results in this study were reassuring. There were no adverse events associated with the gene therapy and no indication of possible precancer cell proliferation.

As expected, patients experienced busulfan-related neutropenia and thrombocytopenia but recovered without any intervention. And 3 patients developed febrile neutropenia that responded to empiric antimicrobial therapy.

“While additional clinical experience and follow-up is needed, these promising results suggest gene therapy should be considered as an early treatment for patients in order to minimize or prevent the life-threatening organ damage that occurs when bone marrow transplant therapy fails to provide a sufficient immune response,” Dr Sorrentino said.

To that end, St. Jude has opened a gene therapy trial using the same lentiviral vector and busulfan conditioning for newly identified infants with SCID-X1 who lack a genetically matched sibling HSC donor.

“Based on the safety and health benefits for older patients reported in this study, we hope this novel gene therapy will help improve immune functioning and transform the lives of younger patients with this devastating disease,” Dr Sorrentino said.

Vials of drug

Photo by Bill Branson

The thrombopoietin receptor agonist romiplostim can produce durable platelet responses in children with symptomatic chronic immune thrombocytopenia (ITP), according to a phase 3 study.

Fifty-two percent of patients who received romiplostim achieved a durable platelet response, compared to 10% of placebo-treated patients.

Investigators said these results suggest romiplostim may be a treatment option for this patient population.

“The results of this study suggest that romiplostim could reduce the frequency and severity of bleeding events for children suffering from symptomatic ITP, thus providing them with another potential treatment option,” said Michael D. Tarantino, MD, of the University of Illinois College of Medicine-Peoria.

Dr Tarantino and his colleagues reported the results in The Lancet. The study was supported by Amgen, which markets romiplostim (Nplate) as a treatment for adults with chronic ITP.

This double-blind study included 62 children (ages 6 to 14) who had ITP for more than 6 months and were randomized to weekly romiplostim (n=42) or placebo (n=20) for 24 weeks. Baseline characteristics were well-balanced between the treatment arms.

The median time since ITP diagnosis was about 2 years for both arms, and the median age at diagnosis was about 7. The median baseline platelet counts were 17.8 x 10⁹/L in the romiplostim arm and 17.7 x 10⁹/L in the placebo arm.

Durable platelet response, the primary endpoint of the study, was defined as achieving weekly platelet responses without rescue medication in at least 6 of the final 8 weeks of the study.

The rates of durable platelet response were 52% (22/42) in the romiplostim arm and 10% (2/20) in the placebo arm (P=0.002, odds ratio 9.1, 95% CI: 1.9, 43.2).

The rates of overall platelet response were 71% (30/42) in the romiplostim arm and 20% in the placebo arm (P=0.0002, odds ratio 9.0, 95% CI: 2.5, 32.3), and the rates of any platelet response were 81% (34/42) and 55% (11/20), respectively (P=0.0313).

The most frequently reported adverse events (AEs) observed in patients receiving romiplostim were contusion (50%), epistaxis (48%), headache (43%), and upper respiratory tract infection (38%).

Oropharyngeal pain occurred more frequently with romiplostim than placebo—26.2% (11/42) and 5.3% (1/19), respectively.

In the 11 romiplostim-treated patients with oropharyngeal pain, streptococcal pharyngitis (n=2), allergic rhinitis (n=2), gastroesophageal reflux (n=1), and serum sickness from IVIg (n=1) were also reported. No oropharyngeal pain AEs were serious or considered treatment-related.

Serious AEs occurred in 23.8% of romiplostim-treated patients and 5.3% of placebo-treated patients.

Serious AEs in the romiplostim arm included epistaxis (n=2), contusion (n=2), headache (n=2), bronchiolitis (n=1), nausea (n=1), petechiae (n=1), epilepsy (n=1), fever (n=1), thrombocytosis (n=1), urinary tract infection (n=1), and vomiting (n=1).

One subject with treatment-related serious AEs experienced headache and thrombocytosis, which did not recur when romiplostim was restarted.

There were no thrombotic events, none of the patients withdrew due to AEs, and none died.

“These data are important in understanding how Nplate may play a role in helping children manage this disease,” said Sean E. Harper, MD, executive vice president of research and development at Amgen.

“We will work with regulatory authorities towards an approval for Nplate for pediatric patients.”

Vials of drug

Photo by Bill Branson

The thrombopoietin receptor agonist romiplostim can produce durable platelet responses in children with symptomatic chronic immune thrombocytopenia (ITP), according to a phase 3 study.

Fifty-two percent of patients who received romiplostim achieved a durable platelet response, compared to 10% of placebo-treated patients.

Investigators said these results suggest romiplostim may be a treatment option for this patient population.

“The results of this study suggest that romiplostim could reduce the frequency and severity of bleeding events for children suffering from symptomatic ITP, thus providing them with another potential treatment option,” said Michael D. Tarantino, MD, of the University of Illinois College of Medicine-Peoria.

Dr Tarantino and his colleagues reported the results in The Lancet. The study was supported by Amgen, which markets romiplostim (Nplate) as a treatment for adults with chronic ITP.

This double-blind study included 62 children (ages 6 to 14) who had ITP for more than 6 months and were randomized to weekly romiplostim (n=42) or placebo (n=20) for 24 weeks. Baseline characteristics were well-balanced between the treatment arms.

The median time since ITP diagnosis was about 2 years for both arms, and the median age at diagnosis was about 7. The median baseline platelet counts were 17.8 x 10⁹/L in the romiplostim arm and 17.7 x 10⁹/L in the placebo arm.

Durable platelet response, the primary endpoint of the study, was defined as achieving weekly platelet responses without rescue medication in at least 6 of the final 8 weeks of the study.

The rates of durable platelet response were 52% (22/42) in the romiplostim arm and 10% (2/20) in the placebo arm (P=0.002, odds ratio 9.1, 95% CI: 1.9, 43.2).

The rates of overall platelet response were 71% (30/42) in the romiplostim arm and 20% in the placebo arm (P=0.0002, odds ratio 9.0, 95% CI: 2.5, 32.3), and the rates of any platelet response were 81% (34/42) and 55% (11/20), respectively (P=0.0313).

The most frequently reported adverse events (AEs) observed in patients receiving romiplostim were contusion (50%), epistaxis (48%), headache (43%), and upper respiratory tract infection (38%).

Oropharyngeal pain occurred more frequently with romiplostim than placebo—26.2% (11/42) and 5.3% (1/19), respectively.

In the 11 romiplostim-treated patients with oropharyngeal pain, streptococcal pharyngitis (n=2), allergic rhinitis (n=2), gastroesophageal reflux (n=1), and serum sickness from IVIg (n=1) were also reported. No oropharyngeal pain AEs were serious or considered treatment-related.

Serious AEs occurred in 23.8% of romiplostim-treated patients and 5.3% of placebo-treated patients.

Serious AEs in the romiplostim arm included epistaxis (n=2), contusion (n=2), headache (n=2), bronchiolitis (n=1), nausea (n=1), petechiae (n=1), epilepsy (n=1), fever (n=1), thrombocytosis (n=1), urinary tract infection (n=1), and vomiting (n=1).

One subject with treatment-related serious AEs experienced headache and thrombocytosis, which did not recur when romiplostim was restarted.

There were no thrombotic events, none of the patients withdrew due to AEs, and none died.

“These data are important in understanding how Nplate may play a role in helping children manage this disease,” said Sean E. Harper, MD, executive vice president of research and development at Amgen.

“We will work with regulatory authorities towards an approval for Nplate for pediatric patients.”

Vials of drug

Photo by Bill Branson

The thrombopoietin receptor agonist romiplostim can produce durable platelet responses in children with symptomatic chronic immune thrombocytopenia (ITP), according to a phase 3 study.

Fifty-two percent of patients who received romiplostim achieved a durable platelet response, compared to 10% of placebo-treated patients.

Investigators said these results suggest romiplostim may be a treatment option for this patient population.

“The results of this study suggest that romiplostim could reduce the frequency and severity of bleeding events for children suffering from symptomatic ITP, thus providing them with another potential treatment option,” said Michael D. Tarantino, MD, of the University of Illinois College of Medicine-Peoria.

Dr Tarantino and his colleagues reported the results in The Lancet. The study was supported by Amgen, which markets romiplostim (Nplate) as a treatment for adults with chronic ITP.

This double-blind study included 62 children (ages 6 to 14) who had ITP for more than 6 months and were randomized to weekly romiplostim (n=42) or placebo (n=20) for 24 weeks. Baseline characteristics were well-balanced between the treatment arms.

The median time since ITP diagnosis was about 2 years for both arms, and the median age at diagnosis was about 7. The median baseline platelet counts were 17.8 x 10⁹/L in the romiplostim arm and 17.7 x 10⁹/L in the placebo arm.

Durable platelet response, the primary endpoint of the study, was defined as achieving weekly platelet responses without rescue medication in at least 6 of the final 8 weeks of the study.

The rates of durable platelet response were 52% (22/42) in the romiplostim arm and 10% (2/20) in the placebo arm (P=0.002, odds ratio 9.1, 95% CI: 1.9, 43.2).

The rates of overall platelet response were 71% (30/42) in the romiplostim arm and 20% in the placebo arm (P=0.0002, odds ratio 9.0, 95% CI: 2.5, 32.3), and the rates of any platelet response were 81% (34/42) and 55% (11/20), respectively (P=0.0313).

The most frequently reported adverse events (AEs) observed in patients receiving romiplostim were contusion (50%), epistaxis (48%), headache (43%), and upper respiratory tract infection (38%).

Oropharyngeal pain occurred more frequently with romiplostim than placebo—26.2% (11/42) and 5.3% (1/19), respectively.

In the 11 romiplostim-treated patients with oropharyngeal pain, streptococcal pharyngitis (n=2), allergic rhinitis (n=2), gastroesophageal reflux (n=1), and serum sickness from IVIg (n=1) were also reported. No oropharyngeal pain AEs were serious or considered treatment-related.

Serious AEs occurred in 23.8% of romiplostim-treated patients and 5.3% of placebo-treated patients.

Serious AEs in the romiplostim arm included epistaxis (n=2), contusion (n=2), headache (n=2), bronchiolitis (n=1), nausea (n=1), petechiae (n=1), epilepsy (n=1), fever (n=1), thrombocytosis (n=1), urinary tract infection (n=1), and vomiting (n=1).

One subject with treatment-related serious AEs experienced headache and thrombocytosis, which did not recur when romiplostim was restarted.

There were no thrombotic events, none of the patients withdrew due to AEs, and none died.

“These data are important in understanding how Nplate may play a role in helping children manage this disease,” said Sean E. Harper, MD, executive vice president of research and development at Amgen.

“We will work with regulatory authorities towards an approval for Nplate for pediatric patients.”