Photo from Penn Medicine

The US Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) has unanimously recommended approval for the chimeric antigen receptor (CAR) T-cell therapy CTL019 (tisagenlecleucel).

The committee voted 10 to 0 in favor of approving CTL019 for the treatment of pediatric and young adult patients (ages 3 to 25) with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

The FDA will consider this vote as it reviews the biologics license application (BLA) for CTL019, but the agency is not obligated to follow the ODAC’s recommendation.

The BLA for CTL019 is supported by results from 3 trials.

This includes a pilot study, which was presented at the 2015 ASH Annual Meeting; the phase 2 ENSIGN trial, which was presented at the 2016 ASH Annual Meeting; and the phase 2 ELIANA study, which was recently presented at the 22nd Congress of the European Hematology Association (EHA).

ELIANA enrolled 88 patients with relapsed/refractory B-cell ALL, and 68 of them received CTL019.

Nine patients did not receive CTL019 due to death or adverse events, 7 patients were affected by manufacturing failures, and 4 patients were pending infusion at last follow-up.

Most of the infused patients (n=65) received lymphodepleting chemotherapy prior to CTL019 (single dose). The median dose was 3.0 × 10⁶ (range, 0.2-5.4 × 10⁶) transduced CTL019 cells/kg.

Sixty-three patients were evaluable for efficacy.

The overall response rate—complete response (CR) plus CR with incomplete hematologic recovery (CRi)—was 83% (52/63). All patients with CR/CRis were minimal residual disease-negative in the bone marrow.

Sixty-eight patients were evaluated for safety.

Serious adverse events occurred in 69% of patients. These included life-threatening cytokine release syndrome (CRS) and hemophagocytic lymphohistiocytosis, neurological events that occurred with CRS or after CRS was resolved, coagulopathies with CRS, and life-threatening infections.

Seventy-eight percent of patients had CRS—21% with grade 3 and 27% with grade 4 CRS. There were no deaths from CRS.

Forty-four percent of patients had neurological toxicities—15% grade 3 or higher. These included encephalopathy, delirium, hallucinations, somnolence, cognitive disorder, seizure, depressed level of consciousness, mental status changes, dysphagia, muscular weakness, and dysarthria.

Severe infectious complications occurred in 26% of patients, and 3 patients died of such complications.

Eleven patients died after receiving CTL019—7 due to ALL, 1 from cerebral hemorrhage, 1 from encephalitis, 1 from a respiratory tract infection, and 1 from systemic mycosis.

Photo from Penn Medicine

The US Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) has unanimously recommended approval for the chimeric antigen receptor (CAR) T-cell therapy CTL019 (tisagenlecleucel).

The committee voted 10 to 0 in favor of approving CTL019 for the treatment of pediatric and young adult patients (ages 3 to 25) with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

The FDA will consider this vote as it reviews the biologics license application (BLA) for CTL019, but the agency is not obligated to follow the ODAC’s recommendation.

The BLA for CTL019 is supported by results from 3 trials.

This includes a pilot study, which was presented at the 2015 ASH Annual Meeting; the phase 2 ENSIGN trial, which was presented at the 2016 ASH Annual Meeting; and the phase 2 ELIANA study, which was recently presented at the 22nd Congress of the European Hematology Association (EHA).

ELIANA enrolled 88 patients with relapsed/refractory B-cell ALL, and 68 of them received CTL019.

Nine patients did not receive CTL019 due to death or adverse events, 7 patients were affected by manufacturing failures, and 4 patients were pending infusion at last follow-up.

Most of the infused patients (n=65) received lymphodepleting chemotherapy prior to CTL019 (single dose). The median dose was 3.0 × 10⁶ (range, 0.2-5.4 × 10⁶) transduced CTL019 cells/kg.

Sixty-three patients were evaluable for efficacy.

The overall response rate—complete response (CR) plus CR with incomplete hematologic recovery (CRi)—was 83% (52/63). All patients with CR/CRis were minimal residual disease-negative in the bone marrow.

Sixty-eight patients were evaluated for safety.

Serious adverse events occurred in 69% of patients. These included life-threatening cytokine release syndrome (CRS) and hemophagocytic lymphohistiocytosis, neurological events that occurred with CRS or after CRS was resolved, coagulopathies with CRS, and life-threatening infections.

Seventy-eight percent of patients had CRS—21% with grade 3 and 27% with grade 4 CRS. There were no deaths from CRS.

Forty-four percent of patients had neurological toxicities—15% grade 3 or higher. These included encephalopathy, delirium, hallucinations, somnolence, cognitive disorder, seizure, depressed level of consciousness, mental status changes, dysphagia, muscular weakness, and dysarthria.

Severe infectious complications occurred in 26% of patients, and 3 patients died of such complications.

Eleven patients died after receiving CTL019—7 due to ALL, 1 from cerebral hemorrhage, 1 from encephalitis, 1 from a respiratory tract infection, and 1 from systemic mycosis.

Photo from Penn Medicine

The US Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) has unanimously recommended approval for the chimeric antigen receptor (CAR) T-cell therapy CTL019 (tisagenlecleucel).

The committee voted 10 to 0 in favor of approving CTL019 for the treatment of pediatric and young adult patients (ages 3 to 25) with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

The FDA will consider this vote as it reviews the biologics license application (BLA) for CTL019, but the agency is not obligated to follow the ODAC’s recommendation.

The BLA for CTL019 is supported by results from 3 trials.

This includes a pilot study, which was presented at the 2015 ASH Annual Meeting; the phase 2 ENSIGN trial, which was presented at the 2016 ASH Annual Meeting; and the phase 2 ELIANA study, which was recently presented at the 22nd Congress of the European Hematology Association (EHA).

ELIANA enrolled 88 patients with relapsed/refractory B-cell ALL, and 68 of them received CTL019.

Nine patients did not receive CTL019 due to death or adverse events, 7 patients were affected by manufacturing failures, and 4 patients were pending infusion at last follow-up.

Most of the infused patients (n=65) received lymphodepleting chemotherapy prior to CTL019 (single dose). The median dose was 3.0 × 10⁶ (range, 0.2-5.4 × 10⁶) transduced CTL019 cells/kg.

Sixty-three patients were evaluable for efficacy.

The overall response rate—complete response (CR) plus CR with incomplete hematologic recovery (CRi)—was 83% (52/63). All patients with CR/CRis were minimal residual disease-negative in the bone marrow.

Sixty-eight patients were evaluated for safety.

Serious adverse events occurred in 69% of patients. These included life-threatening cytokine release syndrome (CRS) and hemophagocytic lymphohistiocytosis, neurological events that occurred with CRS or after CRS was resolved, coagulopathies with CRS, and life-threatening infections.

Seventy-eight percent of patients had CRS—21% with grade 3 and 27% with grade 4 CRS. There were no deaths from CRS.

Forty-four percent of patients had neurological toxicities—15% grade 3 or higher. These included encephalopathy, delirium, hallucinations, somnolence, cognitive disorder, seizure, depressed level of consciousness, mental status changes, dysphagia, muscular weakness, and dysarthria.

Severe infectious complications occurred in 26% of patients, and 3 patients died of such complications.

Eleven patients died after receiving CTL019—7 due to ALL, 1 from cerebral hemorrhage, 1 from encephalitis, 1 from a respiratory tract infection, and 1 from systemic mycosis.

Photo by Bill Branson

The US Food and Drug Administration’s (FDA) Oncologic Drug Advisory Committee (ODAC) has announced a positive opinion of gemtuzumab ozogamicin (GO, Mylotarg), a drug that was withdrawn from the US market in 2010.

In a vote of 6 to 1, the ODAC concluded that trial results suggest a favorable risk-benefit profile for low-dose GO given in combination with standard chemotherapy to patients with newly diagnosed, CD33-positive acute myeloid leukemia (AML).

The ODAC’s role is to provide recommendations to the FDA. The FDA is expected to make a decision on the biologics license application (BLA) for GO by September 2017.

With this BLA, Pfizer is seeking approval for GO in 2 indications.

One is for GO in combination with standard chemotherapy (daunorubicin and cytarabine) for the treatment of previously untreated, de novo, CD33-positive AML.

The other is for GO monotherapy for CD33-positive AML patients in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy.

GO is an investigational antibody-drug conjugate that consists of the cytotoxic agent calicheamicin attached to a monoclonal antibody targeting CD33.

GO was originally approved under the FDA’s accelerated approval program in 2000 for use as a single agent in patients with CD33-positive AML who had experienced their first relapse and were 60 years of age or older.

In 2010, Pfizer voluntarily withdrew GO from the US market due to the results of a confirmatory phase 3 trial, SWOG S0106.

This trial showed there was no clinical benefit for patients who received GO plus daunorubicin and cytarabine over patients who received only daunorubicin and cytarabine.

In addition, the rate of fatal, treatment-related toxicity was significantly higher in the GO arm of the study.

However, results of subsequent trials suggested that a lower dose of GO was safer.

The current BLA for GO includes data from such a study, known as ALFA-0701.

The ODAC voted that results from ALFA-0701 demonstrated a favorable risk-benefit profile for GO when the drug was given at 3 mg/m² on days 1, 4, and 7 in combination with daunorubicin and cytarabine.

The BLA for GO also includes Pfizer-sponsored studies from the original new drug application for GO and a meta-analysis of patients in 5 randomized, phase 3 studies (including ALFA-0701). These studies span 10 years of research and include more than 4300 patients.

Photo by Bill Branson

The US Food and Drug Administration’s (FDA) Oncologic Drug Advisory Committee (ODAC) has announced a positive opinion of gemtuzumab ozogamicin (GO, Mylotarg), a drug that was withdrawn from the US market in 2010.

In a vote of 6 to 1, the ODAC concluded that trial results suggest a favorable risk-benefit profile for low-dose GO given in combination with standard chemotherapy to patients with newly diagnosed, CD33-positive acute myeloid leukemia (AML).

The ODAC’s role is to provide recommendations to the FDA. The FDA is expected to make a decision on the biologics license application (BLA) for GO by September 2017.

With this BLA, Pfizer is seeking approval for GO in 2 indications.

One is for GO in combination with standard chemotherapy (daunorubicin and cytarabine) for the treatment of previously untreated, de novo, CD33-positive AML.

The other is for GO monotherapy for CD33-positive AML patients in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy.

GO is an investigational antibody-drug conjugate that consists of the cytotoxic agent calicheamicin attached to a monoclonal antibody targeting CD33.

GO was originally approved under the FDA’s accelerated approval program in 2000 for use as a single agent in patients with CD33-positive AML who had experienced their first relapse and were 60 years of age or older.

In 2010, Pfizer voluntarily withdrew GO from the US market due to the results of a confirmatory phase 3 trial, SWOG S0106.

This trial showed there was no clinical benefit for patients who received GO plus daunorubicin and cytarabine over patients who received only daunorubicin and cytarabine.

In addition, the rate of fatal, treatment-related toxicity was significantly higher in the GO arm of the study.

However, results of subsequent trials suggested that a lower dose of GO was safer.

The current BLA for GO includes data from such a study, known as ALFA-0701.

The ODAC voted that results from ALFA-0701 demonstrated a favorable risk-benefit profile for GO when the drug was given at 3 mg/m² on days 1, 4, and 7 in combination with daunorubicin and cytarabine.

The BLA for GO also includes Pfizer-sponsored studies from the original new drug application for GO and a meta-analysis of patients in 5 randomized, phase 3 studies (including ALFA-0701). These studies span 10 years of research and include more than 4300 patients.

Photo by Bill Branson

The US Food and Drug Administration’s (FDA) Oncologic Drug Advisory Committee (ODAC) has announced a positive opinion of gemtuzumab ozogamicin (GO, Mylotarg), a drug that was withdrawn from the US market in 2010.

In a vote of 6 to 1, the ODAC concluded that trial results suggest a favorable risk-benefit profile for low-dose GO given in combination with standard chemotherapy to patients with newly diagnosed, CD33-positive acute myeloid leukemia (AML).

The ODAC’s role is to provide recommendations to the FDA. The FDA is expected to make a decision on the biologics license application (BLA) for GO by September 2017.

With this BLA, Pfizer is seeking approval for GO in 2 indications.

One is for GO in combination with standard chemotherapy (daunorubicin and cytarabine) for the treatment of previously untreated, de novo, CD33-positive AML.

The other is for GO monotherapy for CD33-positive AML patients in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy.

GO is an investigational antibody-drug conjugate that consists of the cytotoxic agent calicheamicin attached to a monoclonal antibody targeting CD33.

GO was originally approved under the FDA’s accelerated approval program in 2000 for use as a single agent in patients with CD33-positive AML who had experienced their first relapse and were 60 years of age or older.

In 2010, Pfizer voluntarily withdrew GO from the US market due to the results of a confirmatory phase 3 trial, SWOG S0106.

This trial showed there was no clinical benefit for patients who received GO plus daunorubicin and cytarabine over patients who received only daunorubicin and cytarabine.

In addition, the rate of fatal, treatment-related toxicity was significantly higher in the GO arm of the study.

However, results of subsequent trials suggested that a lower dose of GO was safer.

The current BLA for GO includes data from such a study, known as ALFA-0701.

The ODAC voted that results from ALFA-0701 demonstrated a favorable risk-benefit profile for GO when the drug was given at 3 mg/m² on days 1, 4, and 7 in combination with daunorubicin and cytarabine.

The BLA for GO also includes Pfizer-sponsored studies from the original new drug application for GO and a meta-analysis of patients in 5 randomized, phase 3 studies (including ALFA-0701). These studies span 10 years of research and include more than 4300 patients.

The FP diagnosed urticaria pigmentosa. If urticaria pigmentosa is suspected, it is helpful to stroke the lesion with a fingernail or the wooden end of a cotton-tipped applicator. This induces erythema and a wheal that is confined to the stroked site within the lesion—a positive Darier sign.

Urticaria pigmentosa is a form of mast cell activation syndrome (MCAS), in which there are too many mast cells in the skin. More serious forms of MCAS in adults include systemic mastocytosis and cutaneous mastocytosis. Urticaria pigmentosa is a self-limiting problem in young children that rarely causes sufficient symptoms to warrant treatment.

In this case, the FP assured the mother that this was not dangerous and would go away over time on its own. The FP wrote down the name of the condition for the mother and explained to her that if she noticed any changes or new symptoms, she should return for further evaluation and treatment. The mother was satisfied with this explanation.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Urticaria and angioedema. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 863-870.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP diagnosed urticaria pigmentosa. If urticaria pigmentosa is suspected, it is helpful to stroke the lesion with a fingernail or the wooden end of a cotton-tipped applicator. This induces erythema and a wheal that is confined to the stroked site within the lesion—a positive Darier sign.

Urticaria pigmentosa is a form of mast cell activation syndrome (MCAS), in which there are too many mast cells in the skin. More serious forms of MCAS in adults include systemic mastocytosis and cutaneous mastocytosis. Urticaria pigmentosa is a self-limiting problem in young children that rarely causes sufficient symptoms to warrant treatment.

In this case, the FP assured the mother that this was not dangerous and would go away over time on its own. The FP wrote down the name of the condition for the mother and explained to her that if she noticed any changes or new symptoms, she should return for further evaluation and treatment. The mother was satisfied with this explanation.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Urticaria and angioedema. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 863-870.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP diagnosed urticaria pigmentosa. If urticaria pigmentosa is suspected, it is helpful to stroke the lesion with a fingernail or the wooden end of a cotton-tipped applicator. This induces erythema and a wheal that is confined to the stroked site within the lesion—a positive Darier sign.

Urticaria pigmentosa is a form of mast cell activation syndrome (MCAS), in which there are too many mast cells in the skin. More serious forms of MCAS in adults include systemic mastocytosis and cutaneous mastocytosis. Urticaria pigmentosa is a self-limiting problem in young children that rarely causes sufficient symptoms to warrant treatment.

In this case, the FP assured the mother that this was not dangerous and would go away over time on its own. The FP wrote down the name of the condition for the mother and explained to her that if she noticed any changes or new symptoms, she should return for further evaluation and treatment. The mother was satisfied with this explanation.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Urticaria and angioedema. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 863-870.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The answer to the billion dollar question – Does the chimeric antigen receptor T-cell (CAR T) construct CTL019 (tisagenlecleucel-T) have a favorable risk-benefit profile for the treatment of children and young adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia? – was a unanimous “yes” at a July 12 meeting of the Food and Drug Administration’s Oncologic Drugs Advisory Committee.

“This is the most exciting thing I have seen in my lifetime, and probably since the introduction of ‘multiagent total cancer care,’ as it was called then, for treatment of childhood leukemia,” remarked Timothy P. Cripe, MD, PhD, from Nationwide Children’s Hospital in Columbus, Ohio, and a temporary voting member of the ODAC.

Catherine M. Bollard, MD, MBChB, from the Children’s National Medical Center in Washington, also a temporary ODAC member, said that she voted “yes” because “this is a very poor-risk patient population, this is an unmet need in the pediatric population, and as you saw in the data [presented to ODAC] today, the clinical responses are remarkable. I think Novartis [the maker of CTL019] has done a great job putting together a plan for mitigating risk going forward.”

CTL019 was shown in a pivotal phase 2 clinical trial to induce an overall remission rate of 83% in children and young adults with relapsed/refractory ALL for whom at least two prior lines of therapy had failed. Based on these results, the FDA accepted a biologics license application for the agent from Novartis.

At the meeting, panel members initially seemed favorably disposed toward recommending approval but heard concerns from FDA scientists about the potential for severe or fatal adverse events such as the cytokine release syndrome (CRS); the possible generation of replication competent retrovirus (RCR); and the potential for secondary malignancies from insertional mutagenesis, the incorporation of portions of the lentiviral vector into the patient’s genome.

In his opening remarks, Wilson W. Bryan, MD, from the FDA’s Office of Tissue and Advanced Therapies and Center for Biologics Evaluation and Drug Research, commented that “the clinical development of tisagenlecleucel suggests that this is a life-saving product.”

He went on, however, to frame the FDA’s concerns: “Clinical trials are not always a good predictor of the effectiveness and safety of a marketed product,” he said. “In particular, we are concerned that the same benefit and safety seen in clinical trials may not carry over to routine clinical use.”

The purpose of the hearing was to focus on manufacturing issues related to product quality, including replicability of the product for commercial use and safety issues such as prevention of CRS and neurotoxicities.

“We are also concerned about the hypothetical risk of secondary malignancies. Therefore, we are asking for the committee’s recommendations regarding the nature and duration of follow-up of patients who would receive this product,” Dr. Bryan said.

“CTL019 is a living drug, which demonstrates activity after a single infusion,” said Samit Hirawat, MD, head of oncology global development for Novartis.

But the nature of CTL019 as a living drug also means that it is subject to variations in the ability of autologous T cells harvested via leukapheresis to be infected with the lentiviral vector and expanded into a population of CAR T cells large enough to have therapeutic value, said Xiaobin Victor Lu, PhD, a chemistry, manufacturing, and controls reviewer for the FDA.

Mitigation plan

Novartis’ proposed plan includes specific, long-term steps for mitigating the risk of CRS and neurologic events, such as cerebral edema, the latter of which caused the FDA to call for a clinical hold of the phase 2 ROCKET trial for a different CAR T-cell construct.

Among the proposed elements of the mitigation plan are a 15-year minimum pharmacovigilance program and long-term safety follow-up for adverse events related to the therapy, efficacy, immunogenicity, transgene persistence of CD19 CAR, and the incidence of second malignancies possibly related to insertional mutagenesis.

Novartis also will train treatment center staff on processes for cell collection, cryopreservation, transport, chain of identity, safety management, and logistics for handling the CAR T-cell product. The company proposes to provide on-site training of personnel on CRS and neurotoxicity risk and management, as well as to offer information to patients and caregivers about the signs and symptoms of adverse events of concern.

Dr. Cripe expressed his concerns that Novartis’ proposal to initially limit the mitigation plan to 30 or 35 treatment sites would create problems of access and economic disparities among patients, and could cause inequities among treatment centers even with the same city.

David Lebwohl, MD, head of the CAR T global program for Novartis, said that the planned number of sites for the mitigation program would be expanded after 6 to 12 months if the CAR T construct receives final approval and clinical implementation goes well.

There was nearly unanimous agreement among the panel members that the planned 15-year follow-up and other mitigation measures would be adequate for detecting serious short- and long-term consequences of CAR T-cell therapy.

Patient/advocate perspective

In the public comment section of the proceedings, panel members were urged to vote in favor of CTL019 by parents of children with ALL, including Don McMahon, whose son Connor received the therapy after multiple relapses, and Tom Whitehead, father of Emily Whitehead, the first patient to receive CAR T cells for ALL.

Both children are alive and doing well.

CTL019 is produced by Novartis.

The answer to the billion dollar question – Does the chimeric antigen receptor T-cell (CAR T) construct CTL019 (tisagenlecleucel-T) have a favorable risk-benefit profile for the treatment of children and young adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia? – was a unanimous “yes” at a July 12 meeting of the Food and Drug Administration’s Oncologic Drugs Advisory Committee.

“This is the most exciting thing I have seen in my lifetime, and probably since the introduction of ‘multiagent total cancer care,’ as it was called then, for treatment of childhood leukemia,” remarked Timothy P. Cripe, MD, PhD, from Nationwide Children’s Hospital in Columbus, Ohio, and a temporary voting member of the ODAC.

Catherine M. Bollard, MD, MBChB, from the Children’s National Medical Center in Washington, also a temporary ODAC member, said that she voted “yes” because “this is a very poor-risk patient population, this is an unmet need in the pediatric population, and as you saw in the data [presented to ODAC] today, the clinical responses are remarkable. I think Novartis [the maker of CTL019] has done a great job putting together a plan for mitigating risk going forward.”

CTL019 was shown in a pivotal phase 2 clinical trial to induce an overall remission rate of 83% in children and young adults with relapsed/refractory ALL for whom at least two prior lines of therapy had failed. Based on these results, the FDA accepted a biologics license application for the agent from Novartis.

At the meeting, panel members initially seemed favorably disposed toward recommending approval but heard concerns from FDA scientists about the potential for severe or fatal adverse events such as the cytokine release syndrome (CRS); the possible generation of replication competent retrovirus (RCR); and the potential for secondary malignancies from insertional mutagenesis, the incorporation of portions of the lentiviral vector into the patient’s genome.

In his opening remarks, Wilson W. Bryan, MD, from the FDA’s Office of Tissue and Advanced Therapies and Center for Biologics Evaluation and Drug Research, commented that “the clinical development of tisagenlecleucel suggests that this is a life-saving product.”

He went on, however, to frame the FDA’s concerns: “Clinical trials are not always a good predictor of the effectiveness and safety of a marketed product,” he said. “In particular, we are concerned that the same benefit and safety seen in clinical trials may not carry over to routine clinical use.”

The purpose of the hearing was to focus on manufacturing issues related to product quality, including replicability of the product for commercial use and safety issues such as prevention of CRS and neurotoxicities.

“We are also concerned about the hypothetical risk of secondary malignancies. Therefore, we are asking for the committee’s recommendations regarding the nature and duration of follow-up of patients who would receive this product,” Dr. Bryan said.

“CTL019 is a living drug, which demonstrates activity after a single infusion,” said Samit Hirawat, MD, head of oncology global development for Novartis.

But the nature of CTL019 as a living drug also means that it is subject to variations in the ability of autologous T cells harvested via leukapheresis to be infected with the lentiviral vector and expanded into a population of CAR T cells large enough to have therapeutic value, said Xiaobin Victor Lu, PhD, a chemistry, manufacturing, and controls reviewer for the FDA.

Mitigation plan

Novartis’ proposed plan includes specific, long-term steps for mitigating the risk of CRS and neurologic events, such as cerebral edema, the latter of which caused the FDA to call for a clinical hold of the phase 2 ROCKET trial for a different CAR T-cell construct.

Among the proposed elements of the mitigation plan are a 15-year minimum pharmacovigilance program and long-term safety follow-up for adverse events related to the therapy, efficacy, immunogenicity, transgene persistence of CD19 CAR, and the incidence of second malignancies possibly related to insertional mutagenesis.

Novartis also will train treatment center staff on processes for cell collection, cryopreservation, transport, chain of identity, safety management, and logistics for handling the CAR T-cell product. The company proposes to provide on-site training of personnel on CRS and neurotoxicity risk and management, as well as to offer information to patients and caregivers about the signs and symptoms of adverse events of concern.

Dr. Cripe expressed his concerns that Novartis’ proposal to initially limit the mitigation plan to 30 or 35 treatment sites would create problems of access and economic disparities among patients, and could cause inequities among treatment centers even with the same city.

David Lebwohl, MD, head of the CAR T global program for Novartis, said that the planned number of sites for the mitigation program would be expanded after 6 to 12 months if the CAR T construct receives final approval and clinical implementation goes well.

There was nearly unanimous agreement among the panel members that the planned 15-year follow-up and other mitigation measures would be adequate for detecting serious short- and long-term consequences of CAR T-cell therapy.

Patient/advocate perspective

In the public comment section of the proceedings, panel members were urged to vote in favor of CTL019 by parents of children with ALL, including Don McMahon, whose son Connor received the therapy after multiple relapses, and Tom Whitehead, father of Emily Whitehead, the first patient to receive CAR T cells for ALL.

Both children are alive and doing well.

CTL019 is produced by Novartis.

The answer to the billion dollar question – Does the chimeric antigen receptor T-cell (CAR T) construct CTL019 (tisagenlecleucel-T) have a favorable risk-benefit profile for the treatment of children and young adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia? – was a unanimous “yes” at a July 12 meeting of the Food and Drug Administration’s Oncologic Drugs Advisory Committee.

“This is the most exciting thing I have seen in my lifetime, and probably since the introduction of ‘multiagent total cancer care,’ as it was called then, for treatment of childhood leukemia,” remarked Timothy P. Cripe, MD, PhD, from Nationwide Children’s Hospital in Columbus, Ohio, and a temporary voting member of the ODAC.

Catherine M. Bollard, MD, MBChB, from the Children’s National Medical Center in Washington, also a temporary ODAC member, said that she voted “yes” because “this is a very poor-risk patient population, this is an unmet need in the pediatric population, and as you saw in the data [presented to ODAC] today, the clinical responses are remarkable. I think Novartis [the maker of CTL019] has done a great job putting together a plan for mitigating risk going forward.”

CTL019 was shown in a pivotal phase 2 clinical trial to induce an overall remission rate of 83% in children and young adults with relapsed/refractory ALL for whom at least two prior lines of therapy had failed. Based on these results, the FDA accepted a biologics license application for the agent from Novartis.

At the meeting, panel members initially seemed favorably disposed toward recommending approval but heard concerns from FDA scientists about the potential for severe or fatal adverse events such as the cytokine release syndrome (CRS); the possible generation of replication competent retrovirus (RCR); and the potential for secondary malignancies from insertional mutagenesis, the incorporation of portions of the lentiviral vector into the patient’s genome.

In his opening remarks, Wilson W. Bryan, MD, from the FDA’s Office of Tissue and Advanced Therapies and Center for Biologics Evaluation and Drug Research, commented that “the clinical development of tisagenlecleucel suggests that this is a life-saving product.”

He went on, however, to frame the FDA’s concerns: “Clinical trials are not always a good predictor of the effectiveness and safety of a marketed product,” he said. “In particular, we are concerned that the same benefit and safety seen in clinical trials may not carry over to routine clinical use.”

The purpose of the hearing was to focus on manufacturing issues related to product quality, including replicability of the product for commercial use and safety issues such as prevention of CRS and neurotoxicities.

“We are also concerned about the hypothetical risk of secondary malignancies. Therefore, we are asking for the committee’s recommendations regarding the nature and duration of follow-up of patients who would receive this product,” Dr. Bryan said.

“CTL019 is a living drug, which demonstrates activity after a single infusion,” said Samit Hirawat, MD, head of oncology global development for Novartis.

But the nature of CTL019 as a living drug also means that it is subject to variations in the ability of autologous T cells harvested via leukapheresis to be infected with the lentiviral vector and expanded into a population of CAR T cells large enough to have therapeutic value, said Xiaobin Victor Lu, PhD, a chemistry, manufacturing, and controls reviewer for the FDA.

Mitigation plan

Novartis’ proposed plan includes specific, long-term steps for mitigating the risk of CRS and neurologic events, such as cerebral edema, the latter of which caused the FDA to call for a clinical hold of the phase 2 ROCKET trial for a different CAR T-cell construct.

Among the proposed elements of the mitigation plan are a 15-year minimum pharmacovigilance program and long-term safety follow-up for adverse events related to the therapy, efficacy, immunogenicity, transgene persistence of CD19 CAR, and the incidence of second malignancies possibly related to insertional mutagenesis.

Novartis also will train treatment center staff on processes for cell collection, cryopreservation, transport, chain of identity, safety management, and logistics for handling the CAR T-cell product. The company proposes to provide on-site training of personnel on CRS and neurotoxicity risk and management, as well as to offer information to patients and caregivers about the signs and symptoms of adverse events of concern.

Dr. Cripe expressed his concerns that Novartis’ proposal to initially limit the mitigation plan to 30 or 35 treatment sites would create problems of access and economic disparities among patients, and could cause inequities among treatment centers even with the same city.

David Lebwohl, MD, head of the CAR T global program for Novartis, said that the planned number of sites for the mitigation program would be expanded after 6 to 12 months if the CAR T construct receives final approval and clinical implementation goes well.

There was nearly unanimous agreement among the panel members that the planned 15-year follow-up and other mitigation measures would be adequate for detecting serious short- and long-term consequences of CAR T-cell therapy.

Patient/advocate perspective

In the public comment section of the proceedings, panel members were urged to vote in favor of CTL019 by parents of children with ALL, including Don McMahon, whose son Connor received the therapy after multiple relapses, and Tom Whitehead, father of Emily Whitehead, the first patient to receive CAR T cells for ALL.

Both children are alive and doing well.

CTL019 is produced by Novartis.

SAN FRANCISCO – For patients who meet criteria for binge eating and who express a desire to lose weight, topiramate or lisdexamfetamine are effective treatment options, according to Judith Walsh, MD.

“Binge eating is the most common eating disorder in the United States,” Dr. Walsh said at the UCSF Annual Advances in Internal Medicine meeting. “The lifetime prevalence is 3.5% in women, compared with 2% in men, and 5%-30% of affected women are obese.”

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the condition is characterized by binge eating episodes during which patients consume larger amounts of food than most people would under similar circumstances. “They feel a lack control over eating, [the notion that] ‘I’m eating and I can’t stop,’” said Dr. Walsh of the UCSF division of internal medicine and the Women’s Center for Excellence. Affected patients engage in the behavior of binge eating more than once per week over a period of at least 3 months, and the episodes typically last fewer than 2 hours.

While therapist-led cognitive-behavioral therapy (CBT) is generally considered to be the mainstay of treatment for binge eating disorder, guidelines from the American Psychiatric Association and the National Institute for Health and Care Excellence are conflicting, she said.

A recent meta-analysis funded by the Agency for Healthcare Research and Quality set out to summarize the benefits and harms of psychological and pharmacologic therapies for adults with binge eating disorder (Ann Intern Med. 2016 Sep 20;165[6]:409-20). The researchers evaluated 34 published trials with a low to medium risk of bias, including 25 placebo-controlled trials and 9 waitlist-controlled psychological trials. The majority of trial participants (77%) were women, their mean body mass index was 28.8 kg/m², and their treatment duration ranged from 6 weeks to 6 months.

The review found that second-generation antidepressants such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline improved abstinence from binge eating (relative risk, 1.67) and depression symptoms (RR, 1.97), but resulted in no weight change. Therapist-led CBT was found to strongly improve abstinence from binge eating (RR, 4.95), but it resulted in no change in depressive symptoms or in weight.

Use of lisdexamfetamine was associated with improved abstinence from binge eating (RR, 2.61) and weight loss of 5.2%-6.3%, while use of topiramate was found in two trials to have a moderate benefit on abstinence from binge eating (by 58%-64% in one trial and by 29%-30% in the other), and weight loss of about 4.9 kg.

“Harms of treatment are generally not reported in the psychological studies, nor in 20 of the 25 pharmacologic studies included in the analysis,” said Dr. Walsh, who was not involved with review. The three trials of lisdexamfetamine found an increased risk of sympathetic nervous system arousal (RR, 4.28), insomnia (RR, 2.8), and GI upset (RR, 2.71).

“So, in adults with binge eating disorder, the primary therapy to increase abstinence is cognitive-behavioral therapy, topiramate, lisdexamfetamine, and second-generation antidepressants,” Dr. Walsh concluded. If reducing weight is a priority, the best available treatment options are topiramate and lisdexamfetamine, she said.

Dr. Walsh reported having no financial disclosures.

[email protected]

SAN FRANCISCO – For patients who meet criteria for binge eating and who express a desire to lose weight, topiramate or lisdexamfetamine are effective treatment options, according to Judith Walsh, MD.

“Binge eating is the most common eating disorder in the United States,” Dr. Walsh said at the UCSF Annual Advances in Internal Medicine meeting. “The lifetime prevalence is 3.5% in women, compared with 2% in men, and 5%-30% of affected women are obese.”

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the condition is characterized by binge eating episodes during which patients consume larger amounts of food than most people would under similar circumstances. “They feel a lack control over eating, [the notion that] ‘I’m eating and I can’t stop,’” said Dr. Walsh of the UCSF division of internal medicine and the Women’s Center for Excellence. Affected patients engage in the behavior of binge eating more than once per week over a period of at least 3 months, and the episodes typically last fewer than 2 hours.

While therapist-led cognitive-behavioral therapy (CBT) is generally considered to be the mainstay of treatment for binge eating disorder, guidelines from the American Psychiatric Association and the National Institute for Health and Care Excellence are conflicting, she said.

A recent meta-analysis funded by the Agency for Healthcare Research and Quality set out to summarize the benefits and harms of psychological and pharmacologic therapies for adults with binge eating disorder (Ann Intern Med. 2016 Sep 20;165[6]:409-20). The researchers evaluated 34 published trials with a low to medium risk of bias, including 25 placebo-controlled trials and 9 waitlist-controlled psychological trials. The majority of trial participants (77%) were women, their mean body mass index was 28.8 kg/m², and their treatment duration ranged from 6 weeks to 6 months.

The review found that second-generation antidepressants such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline improved abstinence from binge eating (relative risk, 1.67) and depression symptoms (RR, 1.97), but resulted in no weight change. Therapist-led CBT was found to strongly improve abstinence from binge eating (RR, 4.95), but it resulted in no change in depressive symptoms or in weight.

Use of lisdexamfetamine was associated with improved abstinence from binge eating (RR, 2.61) and weight loss of 5.2%-6.3%, while use of topiramate was found in two trials to have a moderate benefit on abstinence from binge eating (by 58%-64% in one trial and by 29%-30% in the other), and weight loss of about 4.9 kg.

“Harms of treatment are generally not reported in the psychological studies, nor in 20 of the 25 pharmacologic studies included in the analysis,” said Dr. Walsh, who was not involved with review. The three trials of lisdexamfetamine found an increased risk of sympathetic nervous system arousal (RR, 4.28), insomnia (RR, 2.8), and GI upset (RR, 2.71).

“So, in adults with binge eating disorder, the primary therapy to increase abstinence is cognitive-behavioral therapy, topiramate, lisdexamfetamine, and second-generation antidepressants,” Dr. Walsh concluded. If reducing weight is a priority, the best available treatment options are topiramate and lisdexamfetamine, she said.

Dr. Walsh reported having no financial disclosures.

[email protected]

SAN FRANCISCO – For patients who meet criteria for binge eating and who express a desire to lose weight, topiramate or lisdexamfetamine are effective treatment options, according to Judith Walsh, MD.

“Binge eating is the most common eating disorder in the United States,” Dr. Walsh said at the UCSF Annual Advances in Internal Medicine meeting. “The lifetime prevalence is 3.5% in women, compared with 2% in men, and 5%-30% of affected women are obese.”

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the condition is characterized by binge eating episodes during which patients consume larger amounts of food than most people would under similar circumstances. “They feel a lack control over eating, [the notion that] ‘I’m eating and I can’t stop,’” said Dr. Walsh of the UCSF division of internal medicine and the Women’s Center for Excellence. Affected patients engage in the behavior of binge eating more than once per week over a period of at least 3 months, and the episodes typically last fewer than 2 hours.

While therapist-led cognitive-behavioral therapy (CBT) is generally considered to be the mainstay of treatment for binge eating disorder, guidelines from the American Psychiatric Association and the National Institute for Health and Care Excellence are conflicting, she said.

A recent meta-analysis funded by the Agency for Healthcare Research and Quality set out to summarize the benefits and harms of psychological and pharmacologic therapies for adults with binge eating disorder (Ann Intern Med. 2016 Sep 20;165[6]:409-20). The researchers evaluated 34 published trials with a low to medium risk of bias, including 25 placebo-controlled trials and 9 waitlist-controlled psychological trials. The majority of trial participants (77%) were women, their mean body mass index was 28.8 kg/m², and their treatment duration ranged from 6 weeks to 6 months.

The review found that second-generation antidepressants such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline improved abstinence from binge eating (relative risk, 1.67) and depression symptoms (RR, 1.97), but resulted in no weight change. Therapist-led CBT was found to strongly improve abstinence from binge eating (RR, 4.95), but it resulted in no change in depressive symptoms or in weight.

Use of lisdexamfetamine was associated with improved abstinence from binge eating (RR, 2.61) and weight loss of 5.2%-6.3%, while use of topiramate was found in two trials to have a moderate benefit on abstinence from binge eating (by 58%-64% in one trial and by 29%-30% in the other), and weight loss of about 4.9 kg.

“Harms of treatment are generally not reported in the psychological studies, nor in 20 of the 25 pharmacologic studies included in the analysis,” said Dr. Walsh, who was not involved with review. The three trials of lisdexamfetamine found an increased risk of sympathetic nervous system arousal (RR, 4.28), insomnia (RR, 2.8), and GI upset (RR, 2.71).

“So, in adults with binge eating disorder, the primary therapy to increase abstinence is cognitive-behavioral therapy, topiramate, lisdexamfetamine, and second-generation antidepressants,” Dr. Walsh concluded. If reducing weight is a priority, the best available treatment options are topiramate and lisdexamfetamine, she said.

Dr. Walsh reported having no financial disclosures.

[email protected]

Improving diet over time consistently reduces all-cause and cardiovascular mortality, according to an analysis of two large U.S. databases.

Researchers examined the association between dietary change over a 12-year period (1986-1998) and subsequent mortality during a further 12 years of follow-up (1998-2010), using data for 47,994 women participating in the Nurses’ Health Study and 25,745 men participating in the Health Professionals Follow-Up Study. They calculated dietary quality using three different methods: the Alternate Healthy Eating Index-2010 score, the Alternate Mediterranean Diet score, and the Dietary Approaches to Stop Hypertension (DASH) diet score.

©Lisovskaya/ThinkStock

[email protected]

Improving diet over time consistently reduces all-cause and cardiovascular mortality, according to an analysis of two large U.S. databases.

Researchers examined the association between dietary change over a 12-year period (1986-1998) and subsequent mortality during a further 12 years of follow-up (1998-2010), using data for 47,994 women participating in the Nurses’ Health Study and 25,745 men participating in the Health Professionals Follow-Up Study. They calculated dietary quality using three different methods: the Alternate Healthy Eating Index-2010 score, the Alternate Mediterranean Diet score, and the Dietary Approaches to Stop Hypertension (DASH) diet score.

©Lisovskaya/ThinkStock

[email protected]

Improving diet over time consistently reduces all-cause and cardiovascular mortality, according to an analysis of two large U.S. databases.

Researchers examined the association between dietary change over a 12-year period (1986-1998) and subsequent mortality during a further 12 years of follow-up (1998-2010), using data for 47,994 women participating in the Nurses’ Health Study and 25,745 men participating in the Health Professionals Follow-Up Study. They calculated dietary quality using three different methods: the Alternate Healthy Eating Index-2010 score, the Alternate Mediterranean Diet score, and the Dietary Approaches to Stop Hypertension (DASH) diet score.

©Lisovskaya/ThinkStock

[email protected]

To the Editor:

Temporal triangular alopecia (TTA), a condition first described by Sabouraud¹ in 1905, is a circumscribed nonscarring form of alopecia. Also referred to as congenital triangular alopecia, TTA presents as a triangular or lancet-shaped area of hair loss involving the frontotemporal hairline. Temporal triangular alopecia is characterized histologically by a normal number of miniaturized hair follicles without notable inflammation.² Although the majority of cases arise between birth and 9 years of age,^3,4 rare cases of adult-onset TTA also have been reported.^5,6 Adult-onset cases can cause notable diagnostic confusion and inappropriate treatment, as reported in our patient.

A 25-year-old woman with a history of Hashimoto thyroiditis presented with hair loss affecting the right temporal scalp of 3 years' duration that was first noticed by her husband. The lesion was an asymptomatic, 6×8-cm, roughly lancet-shaped patch of alopecia located on the right temporal scalp, bordering on the frontal hairline (Figure 1). Centrally, the patch appeared almost hairless with a few retained terminal hairs. The frontal hairline was thinned but still present. There was no scaling or erythema, and fine vellus hairs and a few isolated terminal hairs covered the area. The corresponding skin on the contralateral temporal scalp showed normal hair density. The patient insisted that she had normal hair at the affected area until 22 years of age, and she denied a history of trauma or tight hairstyles. Initially diagnosed with alopecia areata by her primary care provider, the patient was treated with topical corticosteroids for 6 months without benefit. She was subsequently referred to a dermatologist who again offered a diagnosis of alopecia areata and treated the lesions with 2 intralesional corticosteroid injections without benefit. No biopsies of the affected area were performed, and the patient was given a trial of topical minoxidil.

The patient consulted a new primary care provider and was diagnosed with scarring alopecia. She was referred to our dermatology department for further treatment. An initial biopsy at the edge of the affected area was interpreted as normal, but after failing additional intralesional corticosteroid injections, she was referred to our hair clinic where another biopsy was performed in the central portion of the lesion. A 4-mm diameter punch biopsy specimen revealed a normal epidermis and dermis; however, in the lower dermis only a single terminal follicle was seen (Figure 2). Sections through the upper dermis (Figure 3) showed that the total number of hairs was normal or nearly normal with at least 22 follicles, but most were vellus and indeterminate hairs with only a single terminal hair. The dermal architecture was otherwise normal. Given the clinical and histologic findings, a diagnosis of TTA was made. Subsequent to the diagnosis, the patient did not pursue any additional treatment options and preferred to style her hair so that the area of TTA remained covered.

The differential diagnosis in adults presenting with a patch of localized alopecia includes alopecia areata, trichotillomania, pressure-induced alopecia, traction alopecia, lichen planopilaris, discoid lupus erythematosus, and rarely TTA. Temporal triangular alopecia is a fairly common, if underreported, nonscarring form of alopecia that mainly affects young children. A PubMed search of articles indexed for MEDLINE using the terms temporal triangular alopecia or congenital triangular alopecia or triangular alopecia documented only 76 cases of TTA including our own, with the majority of patients diagnosed before 9 years of age. Only 2 cases of adult-onset TTA have been reported,^5,6 possibly leading to misdiagnosis of adult patients who present with similar areas of hair loss. As with some prior cases of TTA,^5,7 our patient was misdiagnosed with alopecia areata and scarring alopecia, both treated unsuccessfully before a diagnosis of TTA was considered. Clues to the diagnosis included the location, the lack of change in size and shape, the lack of response to intralesional corticosteroids, and the presence of numerous vellus hairs on the surface. A biopsy of the visibly hairless zone was confirmatory. The normal or nearly normal number of miniaturized hairs in specimens of TTA suggest that topical minoxidil therapy (eg, 5% solution twice daily for at least 6 months) might be useful, but the authors have tried it on a few other patients with clinically typical TTA without discernible benefit. When lesions are small, excision provides a fast and permanent solution to the problem, albeit with the usual risks of minor surgery.

To the Editor:

Temporal triangular alopecia (TTA), a condition first described by Sabouraud¹ in 1905, is a circumscribed nonscarring form of alopecia. Also referred to as congenital triangular alopecia, TTA presents as a triangular or lancet-shaped area of hair loss involving the frontotemporal hairline. Temporal triangular alopecia is characterized histologically by a normal number of miniaturized hair follicles without notable inflammation.² Although the majority of cases arise between birth and 9 years of age,^3,4 rare cases of adult-onset TTA also have been reported.^5,6 Adult-onset cases can cause notable diagnostic confusion and inappropriate treatment, as reported in our patient.

A 25-year-old woman with a history of Hashimoto thyroiditis presented with hair loss affecting the right temporal scalp of 3 years' duration that was first noticed by her husband. The lesion was an asymptomatic, 6×8-cm, roughly lancet-shaped patch of alopecia located on the right temporal scalp, bordering on the frontal hairline (Figure 1). Centrally, the patch appeared almost hairless with a few retained terminal hairs. The frontal hairline was thinned but still present. There was no scaling or erythema, and fine vellus hairs and a few isolated terminal hairs covered the area. The corresponding skin on the contralateral temporal scalp showed normal hair density. The patient insisted that she had normal hair at the affected area until 22 years of age, and she denied a history of trauma or tight hairstyles. Initially diagnosed with alopecia areata by her primary care provider, the patient was treated with topical corticosteroids for 6 months without benefit. She was subsequently referred to a dermatologist who again offered a diagnosis of alopecia areata and treated the lesions with 2 intralesional corticosteroid injections without benefit. No biopsies of the affected area were performed, and the patient was given a trial of topical minoxidil.

The patient consulted a new primary care provider and was diagnosed with scarring alopecia. She was referred to our dermatology department for further treatment. An initial biopsy at the edge of the affected area was interpreted as normal, but after failing additional intralesional corticosteroid injections, she was referred to our hair clinic where another biopsy was performed in the central portion of the lesion. A 4-mm diameter punch biopsy specimen revealed a normal epidermis and dermis; however, in the lower dermis only a single terminal follicle was seen (Figure 2). Sections through the upper dermis (Figure 3) showed that the total number of hairs was normal or nearly normal with at least 22 follicles, but most were vellus and indeterminate hairs with only a single terminal hair. The dermal architecture was otherwise normal. Given the clinical and histologic findings, a diagnosis of TTA was made. Subsequent to the diagnosis, the patient did not pursue any additional treatment options and preferred to style her hair so that the area of TTA remained covered.

The differential diagnosis in adults presenting with a patch of localized alopecia includes alopecia areata, trichotillomania, pressure-induced alopecia, traction alopecia, lichen planopilaris, discoid lupus erythematosus, and rarely TTA. Temporal triangular alopecia is a fairly common, if underreported, nonscarring form of alopecia that mainly affects young children. A PubMed search of articles indexed for MEDLINE using the terms temporal triangular alopecia or congenital triangular alopecia or triangular alopecia documented only 76 cases of TTA including our own, with the majority of patients diagnosed before 9 years of age. Only 2 cases of adult-onset TTA have been reported,^5,6 possibly leading to misdiagnosis of adult patients who present with similar areas of hair loss. As with some prior cases of TTA,^5,7 our patient was misdiagnosed with alopecia areata and scarring alopecia, both treated unsuccessfully before a diagnosis of TTA was considered. Clues to the diagnosis included the location, the lack of change in size and shape, the lack of response to intralesional corticosteroids, and the presence of numerous vellus hairs on the surface. A biopsy of the visibly hairless zone was confirmatory. The normal or nearly normal number of miniaturized hairs in specimens of TTA suggest that topical minoxidil therapy (eg, 5% solution twice daily for at least 6 months) might be useful, but the authors have tried it on a few other patients with clinically typical TTA without discernible benefit. When lesions are small, excision provides a fast and permanent solution to the problem, albeit with the usual risks of minor surgery.

To the Editor:

Temporal triangular alopecia (TTA), a condition first described by Sabouraud¹ in 1905, is a circumscribed nonscarring form of alopecia. Also referred to as congenital triangular alopecia, TTA presents as a triangular or lancet-shaped area of hair loss involving the frontotemporal hairline. Temporal triangular alopecia is characterized histologically by a normal number of miniaturized hair follicles without notable inflammation.² Although the majority of cases arise between birth and 9 years of age,^3,4 rare cases of adult-onset TTA also have been reported.^5,6 Adult-onset cases can cause notable diagnostic confusion and inappropriate treatment, as reported in our patient.

A 25-year-old woman with a history of Hashimoto thyroiditis presented with hair loss affecting the right temporal scalp of 3 years' duration that was first noticed by her husband. The lesion was an asymptomatic, 6×8-cm, roughly lancet-shaped patch of alopecia located on the right temporal scalp, bordering on the frontal hairline (Figure 1). Centrally, the patch appeared almost hairless with a few retained terminal hairs. The frontal hairline was thinned but still present. There was no scaling or erythema, and fine vellus hairs and a few isolated terminal hairs covered the area. The corresponding skin on the contralateral temporal scalp showed normal hair density. The patient insisted that she had normal hair at the affected area until 22 years of age, and she denied a history of trauma or tight hairstyles. Initially diagnosed with alopecia areata by her primary care provider, the patient was treated with topical corticosteroids for 6 months without benefit. She was subsequently referred to a dermatologist who again offered a diagnosis of alopecia areata and treated the lesions with 2 intralesional corticosteroid injections without benefit. No biopsies of the affected area were performed, and the patient was given a trial of topical minoxidil.

The patient consulted a new primary care provider and was diagnosed with scarring alopecia. She was referred to our dermatology department for further treatment. An initial biopsy at the edge of the affected area was interpreted as normal, but after failing additional intralesional corticosteroid injections, she was referred to our hair clinic where another biopsy was performed in the central portion of the lesion. A 4-mm diameter punch biopsy specimen revealed a normal epidermis and dermis; however, in the lower dermis only a single terminal follicle was seen (Figure 2). Sections through the upper dermis (Figure 3) showed that the total number of hairs was normal or nearly normal with at least 22 follicles, but most were vellus and indeterminate hairs with only a single terminal hair. The dermal architecture was otherwise normal. Given the clinical and histologic findings, a diagnosis of TTA was made. Subsequent to the diagnosis, the patient did not pursue any additional treatment options and preferred to style her hair so that the area of TTA remained covered.

The differential diagnosis in adults presenting with a patch of localized alopecia includes alopecia areata, trichotillomania, pressure-induced alopecia, traction alopecia, lichen planopilaris, discoid lupus erythematosus, and rarely TTA. Temporal triangular alopecia is a fairly common, if underreported, nonscarring form of alopecia that mainly affects young children. A PubMed search of articles indexed for MEDLINE using the terms temporal triangular alopecia or congenital triangular alopecia or triangular alopecia documented only 76 cases of TTA including our own, with the majority of patients diagnosed before 9 years of age. Only 2 cases of adult-onset TTA have been reported,^5,6 possibly leading to misdiagnosis of adult patients who present with similar areas of hair loss. As with some prior cases of TTA,^5,7 our patient was misdiagnosed with alopecia areata and scarring alopecia, both treated unsuccessfully before a diagnosis of TTA was considered. Clues to the diagnosis included the location, the lack of change in size and shape, the lack of response to intralesional corticosteroids, and the presence of numerous vellus hairs on the surface. A biopsy of the visibly hairless zone was confirmatory. The normal or nearly normal number of miniaturized hairs in specimens of TTA suggest that topical minoxidil therapy (eg, 5% solution twice daily for at least 6 months) might be useful, but the authors have tried it on a few other patients with clinically typical TTA without discernible benefit. When lesions are small, excision provides a fast and permanent solution to the problem, albeit with the usual risks of minor surgery.

Clostridium difficile infection (CDI) remains a major cause of health care–associated diarrhea in industrialized countries and is a common target of antimicrobial stewardship programs (ASPs).

While the burden of CDI has been well described in tertiary metropolitan hospitals, there is a lack of published evidence from regional and rural hospitals. Our recent study published in the Journal of Hospital Infection explores the effect of an ASP on health care–associated CDI rates and the impact of CDI on length of stay and hospital costs.

Stuart Bond, BPharm, DipPharmPrac, is an antimicrobial stewardship pharmacist based at Wollongong Hospital in New South Wales, Australia.

Clostridium difficile infection (CDI) remains a major cause of health care–associated diarrhea in industrialized countries and is a common target of antimicrobial stewardship programs (ASPs).

While the burden of CDI has been well described in tertiary metropolitan hospitals, there is a lack of published evidence from regional and rural hospitals. Our recent study published in the Journal of Hospital Infection explores the effect of an ASP on health care–associated CDI rates and the impact of CDI on length of stay and hospital costs.

Stuart Bond, BPharm, DipPharmPrac, is an antimicrobial stewardship pharmacist based at Wollongong Hospital in New South Wales, Australia.

Clostridium difficile infection (CDI) remains a major cause of health care–associated diarrhea in industrialized countries and is a common target of antimicrobial stewardship programs (ASPs).

While the burden of CDI has been well described in tertiary metropolitan hospitals, there is a lack of published evidence from regional and rural hospitals. Our recent study published in the Journal of Hospital Infection explores the effect of an ASP on health care–associated CDI rates and the impact of CDI on length of stay and hospital costs.

Stuart Bond, BPharm, DipPharmPrac, is an antimicrobial stewardship pharmacist based at Wollongong Hospital in New South Wales, Australia.

Many surgeons let out a collective cheer recently when the American Board of Surgery announced that, as of 2018, they will no longer have to take a high-stakes, pass-fail exam every 10 years to maintain certification.

The Board also announced, effective immediately, that it’s extending its continuing medical education (CME) reporting cycle from 3 to 5 years and reducing the number of required self-assessment CMEs – lectures and articles with a short quiz at the end – by a third. Surgeons now have to report 150 credits over 5 years, 50 from self-assessment CMEs. Under the old system, it was 90 credits over 3 years, 60 of which had to include self-assessment.

Alternative evaluation options

What’s on the minds of many, though, is what the alternatives to the 10-year exam will be. “That’s the $64,000 question,” said Emery Chen, MD, FACS, a general surgeon in private practice in Lancaster, Calif.

ABS is considering models that have worked well for other medical boards and hopes to roll out the alternative pathways at its winter meeting in January 2018, according to ABS Executive Director Frank Lewis, MD, FACS.

A changing world

Like the country’s many other medical boards, ABS has been under pressure to make its MOC process less burdensome and more useful. A major problem is that general surgery isn’t very general anymore; it covers everything from transplants and bariatrics to trauma, endocrine, and vascular operations and more. Surgeons who have specialized have chafed at being examined every 10 years on areas that are no longer part of their practice and at questions about rare diseases such as multiple endocrine neoplasia I and II.

“They remember that one question that kind of stuck in their craw,” said Carol Scott-Conner, MD, FACS, emeritus professor and former head of surgery at the University of Iowa, Iowa City. At one point in her career, Dr. Scott-Conner helped write questions for the exam. “It wasn’t designed to be tricky, but, if you were not practicing in all these fields,” it was tough. “What you’re tested on should be relevant to your practice and help you get better at what you are doing. I think it’s a good change,” she said.

The group will be at national and regional medical meetings this summer and fall to ask surgeons, in person, what they want their MOC system to be. There might be surveys as well, and ABS plans to be at the ACS Clinical Congress in October to solicit input.

The Board is looking to help surgeons with multiple certificates, whether from ABS or other boards, as well. “If we can create a more flexible assessment program that helps them maintain all their certifications, that’s what we want to do. We are looking at options to make it easier for them,” said ABS Director of Communications and Public Affairs Christine Shiffer, who noted that ABS will still likely require a 12-month case log every 10 years, even if surgeons opt out of the 10-year exam.

Will the new system have a negative impact on patient outcomes? After all, even specialized surgeons take night call sometimes. “ABS is responsible to surgeons but also the American public. If we say somebody is certified, it has to mean something. People would argue that there’s no real evidence that the recertification process improves surgical competence. Time will tell,” Dr. Scott-Conner said.

Dr. Lewis said he doesn’t know if the changes will save any money on MOC but noted that, instead of one $1,600 fee every 10 years, there’ll be an option to spread payments out.

Dr. Hughes is on the editorial advisory board of this publication.

[email protected]

Many surgeons let out a collective cheer recently when the American Board of Surgery announced that, as of 2018, they will no longer have to take a high-stakes, pass-fail exam every 10 years to maintain certification.

The Board also announced, effective immediately, that it’s extending its continuing medical education (CME) reporting cycle from 3 to 5 years and reducing the number of required self-assessment CMEs – lectures and articles with a short quiz at the end – by a third. Surgeons now have to report 150 credits over 5 years, 50 from self-assessment CMEs. Under the old system, it was 90 credits over 3 years, 60 of which had to include self-assessment.

Alternative evaluation options

What’s on the minds of many, though, is what the alternatives to the 10-year exam will be. “That’s the $64,000 question,” said Emery Chen, MD, FACS, a general surgeon in private practice in Lancaster, Calif.

ABS is considering models that have worked well for other medical boards and hopes to roll out the alternative pathways at its winter meeting in January 2018, according to ABS Executive Director Frank Lewis, MD, FACS.

A changing world

Like the country’s many other medical boards, ABS has been under pressure to make its MOC process less burdensome and more useful. A major problem is that general surgery isn’t very general anymore; it covers everything from transplants and bariatrics to trauma, endocrine, and vascular operations and more. Surgeons who have specialized have chafed at being examined every 10 years on areas that are no longer part of their practice and at questions about rare diseases such as multiple endocrine neoplasia I and II.

“They remember that one question that kind of stuck in their craw,” said Carol Scott-Conner, MD, FACS, emeritus professor and former head of surgery at the University of Iowa, Iowa City. At one point in her career, Dr. Scott-Conner helped write questions for the exam. “It wasn’t designed to be tricky, but, if you were not practicing in all these fields,” it was tough. “What you’re tested on should be relevant to your practice and help you get better at what you are doing. I think it’s a good change,” she said.

The group will be at national and regional medical meetings this summer and fall to ask surgeons, in person, what they want their MOC system to be. There might be surveys as well, and ABS plans to be at the ACS Clinical Congress in October to solicit input.

The Board is looking to help surgeons with multiple certificates, whether from ABS or other boards, as well. “If we can create a more flexible assessment program that helps them maintain all their certifications, that’s what we want to do. We are looking at options to make it easier for them,” said ABS Director of Communications and Public Affairs Christine Shiffer, who noted that ABS will still likely require a 12-month case log every 10 years, even if surgeons opt out of the 10-year exam.

Will the new system have a negative impact on patient outcomes? After all, even specialized surgeons take night call sometimes. “ABS is responsible to surgeons but also the American public. If we say somebody is certified, it has to mean something. People would argue that there’s no real evidence that the recertification process improves surgical competence. Time will tell,” Dr. Scott-Conner said.

Dr. Lewis said he doesn’t know if the changes will save any money on MOC but noted that, instead of one $1,600 fee every 10 years, there’ll be an option to spread payments out.

Dr. Hughes is on the editorial advisory board of this publication.

[email protected]

Many surgeons let out a collective cheer recently when the American Board of Surgery announced that, as of 2018, they will no longer have to take a high-stakes, pass-fail exam every 10 years to maintain certification.

The Board also announced, effective immediately, that it’s extending its continuing medical education (CME) reporting cycle from 3 to 5 years and reducing the number of required self-assessment CMEs – lectures and articles with a short quiz at the end – by a third. Surgeons now have to report 150 credits over 5 years, 50 from self-assessment CMEs. Under the old system, it was 90 credits over 3 years, 60 of which had to include self-assessment.

Alternative evaluation options

What’s on the minds of many, though, is what the alternatives to the 10-year exam will be. “That’s the $64,000 question,” said Emery Chen, MD, FACS, a general surgeon in private practice in Lancaster, Calif.

ABS is considering models that have worked well for other medical boards and hopes to roll out the alternative pathways at its winter meeting in January 2018, according to ABS Executive Director Frank Lewis, MD, FACS.

A changing world

Like the country’s many other medical boards, ABS has been under pressure to make its MOC process less burdensome and more useful. A major problem is that general surgery isn’t very general anymore; it covers everything from transplants and bariatrics to trauma, endocrine, and vascular operations and more. Surgeons who have specialized have chafed at being examined every 10 years on areas that are no longer part of their practice and at questions about rare diseases such as multiple endocrine neoplasia I and II.

“They remember that one question that kind of stuck in their craw,” said Carol Scott-Conner, MD, FACS, emeritus professor and former head of surgery at the University of Iowa, Iowa City. At one point in her career, Dr. Scott-Conner helped write questions for the exam. “It wasn’t designed to be tricky, but, if you were not practicing in all these fields,” it was tough. “What you’re tested on should be relevant to your practice and help you get better at what you are doing. I think it’s a good change,” she said.

The group will be at national and regional medical meetings this summer and fall to ask surgeons, in person, what they want their MOC system to be. There might be surveys as well, and ABS plans to be at the ACS Clinical Congress in October to solicit input.

The Board is looking to help surgeons with multiple certificates, whether from ABS or other boards, as well. “If we can create a more flexible assessment program that helps them maintain all their certifications, that’s what we want to do. We are looking at options to make it easier for them,” said ABS Director of Communications and Public Affairs Christine Shiffer, who noted that ABS will still likely require a 12-month case log every 10 years, even if surgeons opt out of the 10-year exam.

Will the new system have a negative impact on patient outcomes? After all, even specialized surgeons take night call sometimes. “ABS is responsible to surgeons but also the American public. If we say somebody is certified, it has to mean something. People would argue that there’s no real evidence that the recertification process improves surgical competence. Time will tell,” Dr. Scott-Conner said.

Dr. Lewis said he doesn’t know if the changes will save any money on MOC but noted that, instead of one $1,600 fee every 10 years, there’ll be an option to spread payments out.

Dr. Hughes is on the editorial advisory board of this publication.

[email protected]

Incidence rate ratios of children hospitalized with acute otitis media (hAOM) or more advanced stages, such as mastoidismus and acute mastoiditis (M+AM) declined by 10% and 20%, respectively, after introduction of pneumococcal conjugate vaccines (PCV) in the central region of Denmark, reported Bjarke B. Laursen of Aarhus University in Denmark, and associates.

The use of antibiotics for AOM prior to hospitalization increased markedly during the study period, and that may have impacted the modest reduction in hAOM and M+AM, the researchers said.

copyright luiscar/Thinkstock

Incidence rate ratios of children hospitalized with acute otitis media (hAOM) or more advanced stages, such as mastoidismus and acute mastoiditis (M+AM) declined by 10% and 20%, respectively, after introduction of pneumococcal conjugate vaccines (PCV) in the central region of Denmark, reported Bjarke B. Laursen of Aarhus University in Denmark, and associates.

The use of antibiotics for AOM prior to hospitalization increased markedly during the study period, and that may have impacted the modest reduction in hAOM and M+AM, the researchers said.

copyright luiscar/Thinkstock

Incidence rate ratios of children hospitalized with acute otitis media (hAOM) or more advanced stages, such as mastoidismus and acute mastoiditis (M+AM) declined by 10% and 20%, respectively, after introduction of pneumococcal conjugate vaccines (PCV) in the central region of Denmark, reported Bjarke B. Laursen of Aarhus University in Denmark, and associates.

The use of antibiotics for AOM prior to hospitalization increased markedly during the study period, and that may have impacted the modest reduction in hAOM and M+AM, the researchers said.

copyright luiscar/Thinkstock