The International Guillain-Barré Syndrome Outcome Study (IGOS) is actively recruiting patients with Guillain-Barré Syndrome (GBS) to examine disease course and outcome, according to ClinicalTrials.gov.

IGOS is conducted by the members of the Inflammatory Neuropathy Consortium and Peripheral Nerve Society, and the researchers plan to identify clinical and biological determinants and predictors of disease course and outcome in individual patients with GBS as early as possible after onset of disease. It is a prospective study with standardized collection of clinical data and biomaterials from a large group of well-defined GBS patients during a long follow-up period. Patients will be divided into four cohorts: GBS patients with a follow-up of 1-3 years, normal controls, infectious controls, and other neurological diseases.

The primary outcome is to receive a disability score and Medical Research Council sum score within a 1-year time frame. Secondary outcomes include Overall Neuropathy Limitations Scale, Fatigue Severity Scale, EurQol EQ-5D health questionnaire, and Rasch-built Overall Disability Scale, all in a 1-year time frame. The information will be used to understand the diversity in clinical presentation and response to treatment of GBS and will also be used to develop new prognostic models to predict the clinical course and outcome accurately in individual patients with GBS.

Enrollment for the study started May 2012 and the researchers aim to enroll an estimated 4,000 participants. As of April 2017, the IGOS has enrolled more than 1,500 patients, according to the study’s website. The study is expected to be completed by January 2019. All patients with GBS or variants of GBS, including the Miller Fisher syndrome and overlap syndromes, are eligible for the study.

Currently, patients with GBS have not shown improvement over the last 20 years. It is estimated that 10%-20% of patients remain severely disabled and about 5% die from GBS.

Find the full summary here.

[email protected]

The International Guillain-Barré Syndrome Outcome Study (IGOS) is actively recruiting patients with Guillain-Barré Syndrome (GBS) to examine disease course and outcome, according to ClinicalTrials.gov.

IGOS is conducted by the members of the Inflammatory Neuropathy Consortium and Peripheral Nerve Society, and the researchers plan to identify clinical and biological determinants and predictors of disease course and outcome in individual patients with GBS as early as possible after onset of disease. It is a prospective study with standardized collection of clinical data and biomaterials from a large group of well-defined GBS patients during a long follow-up period. Patients will be divided into four cohorts: GBS patients with a follow-up of 1-3 years, normal controls, infectious controls, and other neurological diseases.

The primary outcome is to receive a disability score and Medical Research Council sum score within a 1-year time frame. Secondary outcomes include Overall Neuropathy Limitations Scale, Fatigue Severity Scale, EurQol EQ-5D health questionnaire, and Rasch-built Overall Disability Scale, all in a 1-year time frame. The information will be used to understand the diversity in clinical presentation and response to treatment of GBS and will also be used to develop new prognostic models to predict the clinical course and outcome accurately in individual patients with GBS.

Enrollment for the study started May 2012 and the researchers aim to enroll an estimated 4,000 participants. As of April 2017, the IGOS has enrolled more than 1,500 patients, according to the study’s website. The study is expected to be completed by January 2019. All patients with GBS or variants of GBS, including the Miller Fisher syndrome and overlap syndromes, are eligible for the study.

Currently, patients with GBS have not shown improvement over the last 20 years. It is estimated that 10%-20% of patients remain severely disabled and about 5% die from GBS.

Find the full summary here.

[email protected]

The International Guillain-Barré Syndrome Outcome Study (IGOS) is actively recruiting patients with Guillain-Barré Syndrome (GBS) to examine disease course and outcome, according to ClinicalTrials.gov.

IGOS is conducted by the members of the Inflammatory Neuropathy Consortium and Peripheral Nerve Society, and the researchers plan to identify clinical and biological determinants and predictors of disease course and outcome in individual patients with GBS as early as possible after onset of disease. It is a prospective study with standardized collection of clinical data and biomaterials from a large group of well-defined GBS patients during a long follow-up period. Patients will be divided into four cohorts: GBS patients with a follow-up of 1-3 years, normal controls, infectious controls, and other neurological diseases.

The primary outcome is to receive a disability score and Medical Research Council sum score within a 1-year time frame. Secondary outcomes include Overall Neuropathy Limitations Scale, Fatigue Severity Scale, EurQol EQ-5D health questionnaire, and Rasch-built Overall Disability Scale, all in a 1-year time frame. The information will be used to understand the diversity in clinical presentation and response to treatment of GBS and will also be used to develop new prognostic models to predict the clinical course and outcome accurately in individual patients with GBS.

Enrollment for the study started May 2012 and the researchers aim to enroll an estimated 4,000 participants. As of April 2017, the IGOS has enrolled more than 1,500 patients, according to the study’s website. The study is expected to be completed by January 2019. All patients with GBS or variants of GBS, including the Miller Fisher syndrome and overlap syndromes, are eligible for the study.

Currently, patients with GBS have not shown improvement over the last 20 years. It is estimated that 10%-20% of patients remain severely disabled and about 5% die from GBS.

Find the full summary here.

[email protected]

To the Editor:

A 41-year-old man presented with a slowly enlarging, tender, firm lesion on the left hallux of approximately 5 months' duration that initially appeared to be a blister. He reported no history of keloids or trauma to the left foot. On examination, a 3.5-cm, flesh-colored, pedunculated, firm nodule was present on the lateral aspect of the left great hallux (Figure 1). No lymphadenopathy was found. The lesion was diagnosed at that time as a keloid and treated with intralesional steroids without response. The patient was lost to follow-up, and after 5 months he presented again with pain and drainage from the lesion. Acute drainage resolved after antibiotic therapy. A shave biopsy was performed, which revealed findings consistent with a dermatofibrosarcoma protuberans (DFSP). A chest radiograph was unremarkable. Re-excision was performed with negative margins on frozen section but with positive peripheral and deep margins on permanent sections. The patient subsequently underwent amputation of the left great toe and was lost to follow-up after the initial postoperative period.

Histopathologic examination demonstrated a polypoid spindle cell tumor that filled the dermis and invaded into the subcutaneous adipose tissue (Figure 2). The spindle cells had tapered nuclei in a honeycomb arrangement with only mild nuclear pleomorphism arranged in fascicles with a herringbone formation. Areas showed a myxoid stroma with abundant mucin (Figure 3). Immunostaining demonstrated cells strongly positive for CD34 and negative for MART (melanoma-associated antigen recognized by T cells), S-100, and smooth muscle actin immunostains.

Dermatofibrosarcoma protuberans is a sarcoma that is locally aggressive and tends to recur after surgical excision, though rare cases of metastasis involving the lungs have been reported.¹² Dermatofibrosarcoma protuberans usually affects young to middle-aged adults. Acral DFSP is rare in adults, with tumors most commonly occurring on the trunk (50%-60%), proximal extremities (20%-30%), or the head and neck (10%-15%).^1,2 A higher rate of acral DFSP has been found in children, which may be due to the increased rate of extremity trauma. Dermatofibrosarcoma protuberans commonly presents as an asymptomatic, slowly growing, indurated plaque that may be flesh colored or hyperpigmented, followed by development of erythematous firm nodules of up to several centimeters.^1,3 Dermatofibrosarcoma protuberans may be associated with a purulent exudate or ulceration, and pain may develop as the lesion grows.

Histopathologic evaluation shows an early plaque stage characterized by low cellularity, minimal nuclear atypia, and rare mitotic figures.⁴ In the nodular stage, the spindle cells are arranged as short fascicles in a storiform arrangement and infiltrate the subcutaneous tissue in a honeycomb pattern with hyperchromatic nuclei and mitotic figures. The nodules may develop myxomatous areas as well as less-differentiated foci with intersecting fascicles in a herringbone pattern. Anti-CD34 antibody immunostaining demonstrates strongly positive spindle cells, while DFSP is negative for stromelysin 3, factor XIIIa, and D2-40, which can help to differentiate DFSP from dermatofibroma.⁵ The myxoid subtype of DFSP does not differ clinically or prognostically from conventional DFSP, though its recognition can be of use in differentiating other myxoid tumors. Myxoid DFSP is nearly always positive for CD34 and negative for the neural marker S-100 protein.⁶

Some reports have demonstrated that Mohs micrographic surgery is superior to wide local excision in treatment of DFSP, as it results in fewer local recurrences and metastases.^7,8 Because of cytogenic abnormalities such as a reciprocal chromosomal (17;22) translocation or supernumerary ring chromosome derived from t(17;22) that place the PDGFB gene under the control of COL1A1 promoter, imatinib mesylate has been tested in DFSP and resulted in dramatic responses in both adults and children.^9,10 Suggested uses of imatinib include metastatic disease and locally invasive disease not suitable for surgical excision as well as a method to debulk tumors prior to resection.¹¹

To the Editor:

A 41-year-old man presented with a slowly enlarging, tender, firm lesion on the left hallux of approximately 5 months' duration that initially appeared to be a blister. He reported no history of keloids or trauma to the left foot. On examination, a 3.5-cm, flesh-colored, pedunculated, firm nodule was present on the lateral aspect of the left great hallux (Figure 1). No lymphadenopathy was found. The lesion was diagnosed at that time as a keloid and treated with intralesional steroids without response. The patient was lost to follow-up, and after 5 months he presented again with pain and drainage from the lesion. Acute drainage resolved after antibiotic therapy. A shave biopsy was performed, which revealed findings consistent with a dermatofibrosarcoma protuberans (DFSP). A chest radiograph was unremarkable. Re-excision was performed with negative margins on frozen section but with positive peripheral and deep margins on permanent sections. The patient subsequently underwent amputation of the left great toe and was lost to follow-up after the initial postoperative period.

Histopathologic examination demonstrated a polypoid spindle cell tumor that filled the dermis and invaded into the subcutaneous adipose tissue (Figure 2). The spindle cells had tapered nuclei in a honeycomb arrangement with only mild nuclear pleomorphism arranged in fascicles with a herringbone formation. Areas showed a myxoid stroma with abundant mucin (Figure 3). Immunostaining demonstrated cells strongly positive for CD34 and negative for MART (melanoma-associated antigen recognized by T cells), S-100, and smooth muscle actin immunostains.

Dermatofibrosarcoma protuberans is a sarcoma that is locally aggressive and tends to recur after surgical excision, though rare cases of metastasis involving the lungs have been reported.¹² Dermatofibrosarcoma protuberans usually affects young to middle-aged adults. Acral DFSP is rare in adults, with tumors most commonly occurring on the trunk (50%-60%), proximal extremities (20%-30%), or the head and neck (10%-15%).^1,2 A higher rate of acral DFSP has been found in children, which may be due to the increased rate of extremity trauma. Dermatofibrosarcoma protuberans commonly presents as an asymptomatic, slowly growing, indurated plaque that may be flesh colored or hyperpigmented, followed by development of erythematous firm nodules of up to several centimeters.^1,3 Dermatofibrosarcoma protuberans may be associated with a purulent exudate or ulceration, and pain may develop as the lesion grows.

Histopathologic evaluation shows an early plaque stage characterized by low cellularity, minimal nuclear atypia, and rare mitotic figures.⁴ In the nodular stage, the spindle cells are arranged as short fascicles in a storiform arrangement and infiltrate the subcutaneous tissue in a honeycomb pattern with hyperchromatic nuclei and mitotic figures. The nodules may develop myxomatous areas as well as less-differentiated foci with intersecting fascicles in a herringbone pattern. Anti-CD34 antibody immunostaining demonstrates strongly positive spindle cells, while DFSP is negative for stromelysin 3, factor XIIIa, and D2-40, which can help to differentiate DFSP from dermatofibroma.⁵ The myxoid subtype of DFSP does not differ clinically or prognostically from conventional DFSP, though its recognition can be of use in differentiating other myxoid tumors. Myxoid DFSP is nearly always positive for CD34 and negative for the neural marker S-100 protein.⁶

Some reports have demonstrated that Mohs micrographic surgery is superior to wide local excision in treatment of DFSP, as it results in fewer local recurrences and metastases.^7,8 Because of cytogenic abnormalities such as a reciprocal chromosomal (17;22) translocation or supernumerary ring chromosome derived from t(17;22) that place the PDGFB gene under the control of COL1A1 promoter, imatinib mesylate has been tested in DFSP and resulted in dramatic responses in both adults and children.^9,10 Suggested uses of imatinib include metastatic disease and locally invasive disease not suitable for surgical excision as well as a method to debulk tumors prior to resection.¹¹

To the Editor:

A 41-year-old man presented with a slowly enlarging, tender, firm lesion on the left hallux of approximately 5 months' duration that initially appeared to be a blister. He reported no history of keloids or trauma to the left foot. On examination, a 3.5-cm, flesh-colored, pedunculated, firm nodule was present on the lateral aspect of the left great hallux (Figure 1). No lymphadenopathy was found. The lesion was diagnosed at that time as a keloid and treated with intralesional steroids without response. The patient was lost to follow-up, and after 5 months he presented again with pain and drainage from the lesion. Acute drainage resolved after antibiotic therapy. A shave biopsy was performed, which revealed findings consistent with a dermatofibrosarcoma protuberans (DFSP). A chest radiograph was unremarkable. Re-excision was performed with negative margins on frozen section but with positive peripheral and deep margins on permanent sections. The patient subsequently underwent amputation of the left great toe and was lost to follow-up after the initial postoperative period.

Histopathologic examination demonstrated a polypoid spindle cell tumor that filled the dermis and invaded into the subcutaneous adipose tissue (Figure 2). The spindle cells had tapered nuclei in a honeycomb arrangement with only mild nuclear pleomorphism arranged in fascicles with a herringbone formation. Areas showed a myxoid stroma with abundant mucin (Figure 3). Immunostaining demonstrated cells strongly positive for CD34 and negative for MART (melanoma-associated antigen recognized by T cells), S-100, and smooth muscle actin immunostains.

Dermatofibrosarcoma protuberans is a sarcoma that is locally aggressive and tends to recur after surgical excision, though rare cases of metastasis involving the lungs have been reported.¹² Dermatofibrosarcoma protuberans usually affects young to middle-aged adults. Acral DFSP is rare in adults, with tumors most commonly occurring on the trunk (50%-60%), proximal extremities (20%-30%), or the head and neck (10%-15%).^1,2 A higher rate of acral DFSP has been found in children, which may be due to the increased rate of extremity trauma. Dermatofibrosarcoma protuberans commonly presents as an asymptomatic, slowly growing, indurated plaque that may be flesh colored or hyperpigmented, followed by development of erythematous firm nodules of up to several centimeters.^1,3 Dermatofibrosarcoma protuberans may be associated with a purulent exudate or ulceration, and pain may develop as the lesion grows.

Histopathologic evaluation shows an early plaque stage characterized by low cellularity, minimal nuclear atypia, and rare mitotic figures.⁴ In the nodular stage, the spindle cells are arranged as short fascicles in a storiform arrangement and infiltrate the subcutaneous tissue in a honeycomb pattern with hyperchromatic nuclei and mitotic figures. The nodules may develop myxomatous areas as well as less-differentiated foci with intersecting fascicles in a herringbone pattern. Anti-CD34 antibody immunostaining demonstrates strongly positive spindle cells, while DFSP is negative for stromelysin 3, factor XIIIa, and D2-40, which can help to differentiate DFSP from dermatofibroma.⁵ The myxoid subtype of DFSP does not differ clinically or prognostically from conventional DFSP, though its recognition can be of use in differentiating other myxoid tumors. Myxoid DFSP is nearly always positive for CD34 and negative for the neural marker S-100 protein.⁶

Some reports have demonstrated that Mohs micrographic surgery is superior to wide local excision in treatment of DFSP, as it results in fewer local recurrences and metastases.^7,8 Because of cytogenic abnormalities such as a reciprocal chromosomal (17;22) translocation or supernumerary ring chromosome derived from t(17;22) that place the PDGFB gene under the control of COL1A1 promoter, imatinib mesylate has been tested in DFSP and resulted in dramatic responses in both adults and children.^9,10 Suggested uses of imatinib include metastatic disease and locally invasive disease not suitable for surgical excision as well as a method to debulk tumors prior to resection.¹¹

Use of Pap smears and mammography has slowly but steadily declined since both peaked in the year 2000, according to the National Center for Health Statistics.

The age-adjusted rate of women aged 18 years and over who reported having had a Pap smear in the past 3 years dropped from 81.3% in 2000 to 70.2% in 2015. Over that same time period, the age-adjusted rate of women aged 40 years and over who had a mammogram over the previous 2 years declined from 70.4% in 2000 to 64% in 2015, the NCHS reported in “Health, United States, 2016.”

[email protected]

Use of Pap smears and mammography has slowly but steadily declined since both peaked in the year 2000, according to the National Center for Health Statistics.

The age-adjusted rate of women aged 18 years and over who reported having had a Pap smear in the past 3 years dropped from 81.3% in 2000 to 70.2% in 2015. Over that same time period, the age-adjusted rate of women aged 40 years and over who had a mammogram over the previous 2 years declined from 70.4% in 2000 to 64% in 2015, the NCHS reported in “Health, United States, 2016.”

[email protected]

Use of Pap smears and mammography has slowly but steadily declined since both peaked in the year 2000, according to the National Center for Health Statistics.

The age-adjusted rate of women aged 18 years and over who reported having had a Pap smear in the past 3 years dropped from 81.3% in 2000 to 70.2% in 2015. Over that same time period, the age-adjusted rate of women aged 40 years and over who had a mammogram over the previous 2 years declined from 70.4% in 2000 to 64% in 2015, the NCHS reported in “Health, United States, 2016.”

[email protected]

American Indians/Alaska Natives have the highest rate of new hepatitis C virus (HCV) infections of all ethnic groups, according to recent surveillance data from CDC.

The IHS has distributed updated guidelines on HCV prevention, testing, and treatment to IHS facilities. The guidelines are based on those of the National Viral Hepatitis Action Plan for 2017-2020, the U.S. Preventive Services Task Force, the CDC, and the American Association for the Study of Liver Diseases.

Tribal programs are an important element of the outreach. In 2015, for instance, the Cherokee Nation became the first tribe in the U.S. to launch an HCV Elimination Project, with the goal of screening 80,000 patients over the next 3 years. Last year, 23,000 patients were screened.

Other programs provide telehealth and teleconsultation services to treat patients on-site, rather than referring them to facilities far from their communities. A pharmacist-led treatment program, for example, in conjunction with a local physician and Project ECHO (Extension for Community Health Outcomes) and telehealth programs, has successfully cured > 10 patients on the Fort Peck reservation.

An estimated 20,000 to 40,000 IHS patients need HCV treatment. The IHS encourages anyone with HCV—even those who had unsuccessful treatment in the past—to seek care as soon as possible.

American Indians/Alaska Natives have the highest rate of new hepatitis C virus (HCV) infections of all ethnic groups, according to recent surveillance data from CDC.

The IHS has distributed updated guidelines on HCV prevention, testing, and treatment to IHS facilities. The guidelines are based on those of the National Viral Hepatitis Action Plan for 2017-2020, the U.S. Preventive Services Task Force, the CDC, and the American Association for the Study of Liver Diseases.

Tribal programs are an important element of the outreach. In 2015, for instance, the Cherokee Nation became the first tribe in the U.S. to launch an HCV Elimination Project, with the goal of screening 80,000 patients over the next 3 years. Last year, 23,000 patients were screened.

Other programs provide telehealth and teleconsultation services to treat patients on-site, rather than referring them to facilities far from their communities. A pharmacist-led treatment program, for example, in conjunction with a local physician and Project ECHO (Extension for Community Health Outcomes) and telehealth programs, has successfully cured > 10 patients on the Fort Peck reservation.

An estimated 20,000 to 40,000 IHS patients need HCV treatment. The IHS encourages anyone with HCV—even those who had unsuccessful treatment in the past—to seek care as soon as possible.

American Indians/Alaska Natives have the highest rate of new hepatitis C virus (HCV) infections of all ethnic groups, according to recent surveillance data from CDC.

The IHS has distributed updated guidelines on HCV prevention, testing, and treatment to IHS facilities. The guidelines are based on those of the National Viral Hepatitis Action Plan for 2017-2020, the U.S. Preventive Services Task Force, the CDC, and the American Association for the Study of Liver Diseases.

Tribal programs are an important element of the outreach. In 2015, for instance, the Cherokee Nation became the first tribe in the U.S. to launch an HCV Elimination Project, with the goal of screening 80,000 patients over the next 3 years. Last year, 23,000 patients were screened.

Other programs provide telehealth and teleconsultation services to treat patients on-site, rather than referring them to facilities far from their communities. A pharmacist-led treatment program, for example, in conjunction with a local physician and Project ECHO (Extension for Community Health Outcomes) and telehealth programs, has successfully cured > 10 patients on the Fort Peck reservation.

An estimated 20,000 to 40,000 IHS patients need HCV treatment. The IHS encourages anyone with HCV—even those who had unsuccessful treatment in the past—to seek care as soon as possible.

This 58-year-old woman was unaware there was a problem with her neck skin until friends took a picture and showed it to her. She was surprised and distressed, thinking the changes were new and therefore representative of serious disease.

She denies having any associated symptoms but does admit to a great deal of sun exposure over the years. Her history is significant for a basal cell carcinoma, removed from her chest many years ago. She also has a history of smoking and early COPD.

EXAMINATION
A solid sheet of fine, blanchable telangiectasias spreads across the patient’s upper anterior neck, extending down onto her chest. It spares the skin directly under her chin, leaving an unaffected white oval area.

Elsewhere, the patient has a great deal of dermatoheliosis superimposed on her type II skin, including solar lentigines, weathering, and focal solar elastosis.

What is the diagnosis?

PC can manifest with combinations of red, brown, and yellow discoloration around the neck. In this case, the dominant color was red. The oval area of spared skin was created by the shade of the patient’s chin.

Similar changes can be seen with other conditions, such as poikiloderma vasculare atrophicans, a manifestation of small plaque parapsoriasis. However, this typically affects areas below the waist and does not have areas of sparing.

Treatment has been attempted with lasers and peels, yielding mixed success. Because of her condition’s benignancy, this patient did not opt for treatment.

TAKE-HOME LEARNING POINTS

• Poikiloderma of Civatte (PC) is a permanent skin change caused by overexposure to the sun or another UV source; it is more common in women than men.
• PC manifests with mottled hyper- or hypopigmented patches of skin on the anterior neck and upper chest, which develop gradually over the course of decades. Many patients also have sheets of telangiectasias covering the affected area.
• A distinct area of sparing (usually oval) is typically seen on the upper anterior neck, due to the chin’s shading of this area.
• Laser treatment has been somewhat successful in lightening the affected skin.

This 58-year-old woman was unaware there was a problem with her neck skin until friends took a picture and showed it to her. She was surprised and distressed, thinking the changes were new and therefore representative of serious disease.

She denies having any associated symptoms but does admit to a great deal of sun exposure over the years. Her history is significant for a basal cell carcinoma, removed from her chest many years ago. She also has a history of smoking and early COPD.

EXAMINATION
A solid sheet of fine, blanchable telangiectasias spreads across the patient’s upper anterior neck, extending down onto her chest. It spares the skin directly under her chin, leaving an unaffected white oval area.

Elsewhere, the patient has a great deal of dermatoheliosis superimposed on her type II skin, including solar lentigines, weathering, and focal solar elastosis.

What is the diagnosis?

PC can manifest with combinations of red, brown, and yellow discoloration around the neck. In this case, the dominant color was red. The oval area of spared skin was created by the shade of the patient’s chin.

Similar changes can be seen with other conditions, such as poikiloderma vasculare atrophicans, a manifestation of small plaque parapsoriasis. However, this typically affects areas below the waist and does not have areas of sparing.

Treatment has been attempted with lasers and peels, yielding mixed success. Because of her condition’s benignancy, this patient did not opt for treatment.

TAKE-HOME LEARNING POINTS

• Poikiloderma of Civatte (PC) is a permanent skin change caused by overexposure to the sun or another UV source; it is more common in women than men.
• PC manifests with mottled hyper- or hypopigmented patches of skin on the anterior neck and upper chest, which develop gradually over the course of decades. Many patients also have sheets of telangiectasias covering the affected area.
• A distinct area of sparing (usually oval) is typically seen on the upper anterior neck, due to the chin’s shading of this area.
• Laser treatment has been somewhat successful in lightening the affected skin.

This 58-year-old woman was unaware there was a problem with her neck skin until friends took a picture and showed it to her. She was surprised and distressed, thinking the changes were new and therefore representative of serious disease.

She denies having any associated symptoms but does admit to a great deal of sun exposure over the years. Her history is significant for a basal cell carcinoma, removed from her chest many years ago. She also has a history of smoking and early COPD.

EXAMINATION
A solid sheet of fine, blanchable telangiectasias spreads across the patient’s upper anterior neck, extending down onto her chest. It spares the skin directly under her chin, leaving an unaffected white oval area.

Elsewhere, the patient has a great deal of dermatoheliosis superimposed on her type II skin, including solar lentigines, weathering, and focal solar elastosis.

What is the diagnosis?

PC can manifest with combinations of red, brown, and yellow discoloration around the neck. In this case, the dominant color was red. The oval area of spared skin was created by the shade of the patient’s chin.

Similar changes can be seen with other conditions, such as poikiloderma vasculare atrophicans, a manifestation of small plaque parapsoriasis. However, this typically affects areas below the waist and does not have areas of sparing.

Treatment has been attempted with lasers and peels, yielding mixed success. Because of her condition’s benignancy, this patient did not opt for treatment.

TAKE-HOME LEARNING POINTS

• Poikiloderma of Civatte (PC) is a permanent skin change caused by overexposure to the sun or another UV source; it is more common in women than men.
• PC manifests with mottled hyper- or hypopigmented patches of skin on the anterior neck and upper chest, which develop gradually over the course of decades. Many patients also have sheets of telangiectasias covering the affected area.
• A distinct area of sparing (usually oval) is typically seen on the upper anterior neck, due to the chin’s shading of this area.
• Laser treatment has been somewhat successful in lightening the affected skin.

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has approved the supplemental biologics license application (sBLA) for blinatumomab (Blincyto®).

The aim of the sBLA was to expand the indication for blinatumomab to include all patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and to convert blinatumomab’s accelerated approval to a full approval.

Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

In 2014, the FDA granted blinatumomab accelerated approval to treat adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory BCP-ALL.

In 2016, the FDA granted the therapy accelerated approval for pediatric patients with Ph- relapsed/refractory BCP-ALL.

Now, the FDA has granted blinatumomab full approval for pediatric and adult patients with Ph- or Ph+ relapsed/refractory BCP-ALL.

The FDA also recently approved the sBLA for blinatumomab to be infused over 7 days with preservative, adding to the previously approved administration options for infusion over 24 and 48 hours (preservative-free).

The blinatumomab intravenous bag for a 7-day infusion contains Bacteriostatic 0.9% Sodium Chloride, USP (containing 0.9% benzyl alcohol), which permits continuous intravenous infusion of blinatumomab at 28 mcg/day or 15 mcg/m²/day for a total of 7 days.

The 7-day infusion is not recommended for patients weighing less than 22 kg due to the risk of serious and sometimes fatal adverse events associated with benzyl alcohol in pediatric patients. See the full prescribing information for details.

The prescribing information for blinatumomab includes a boxed warning detailing the risk of cytokine release syndrome and neurologic toxicities. Blinatumomab is also under a Risk Evaluation and Mitigation Strategy program in the US intended to inform healthcare providers about these risks.

Blinatumomab is marketed by Amgen.

Trial results

With this sBLA, Amgen sought to make blinatumomab available as a treatment for patients with Ph+ relapsed/refractory BCP-ALL (as well as Ph-).

To this end, the application included data from the ALCANTARA study, which were published in the Journal of Clinical Oncology.

In this trial, researchers evaluated blinatumomab in adults with Ph+ relapsed/refractory BCP-ALL who had failed treatment with at least 1 tyrosine kinase inhibitor.

Thirty-six percent of patients achieved a complete response or complete response with partial hematologic recovery within the first 2 cycles of blinatumomab treatment. Of these patients, 88% were minimal residual disease-negative.

The most frequent adverse events (AEs) in this trial were pyrexia (58%), neurologic events (47%), febrile neutropenia (40%), and headache (31%). Three patients had grade 1/2 cytokine release syndrome, and 3 patients had grade 3 neurologic AEs.

The sBLA also included overall survival (OS) data from the phase 3 TOWER trial, which was intended to support the conversion of blinatumomab’s accelerated approval to a full approval.

Results from the TOWER trial were published in NEJM.

In this study, researchers compared blinatumomab to standard of care (SOC) chemotherapy (4 different regimens) in adults with Ph- relapsed/refractory BCP-ALL.

Blinatumomab produced higher response rates and nearly doubled OS compared to SOC. The median OS was 7.7 months in the blinatumomab arm and 4 months in the SOC arm. The hazard ratio for death was 0.71 (P=0.012).

The incidence of grade 3 or higher AEs was higher in the SOC arm, but the incidence of serious AEs was higher in the blinatumomab arm.

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has approved the supplemental biologics license application (sBLA) for blinatumomab (Blincyto®).

The aim of the sBLA was to expand the indication for blinatumomab to include all patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and to convert blinatumomab’s accelerated approval to a full approval.

Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

In 2014, the FDA granted blinatumomab accelerated approval to treat adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory BCP-ALL.

In 2016, the FDA granted the therapy accelerated approval for pediatric patients with Ph- relapsed/refractory BCP-ALL.

Now, the FDA has granted blinatumomab full approval for pediatric and adult patients with Ph- or Ph+ relapsed/refractory BCP-ALL.

The FDA also recently approved the sBLA for blinatumomab to be infused over 7 days with preservative, adding to the previously approved administration options for infusion over 24 and 48 hours (preservative-free).

The blinatumomab intravenous bag for a 7-day infusion contains Bacteriostatic 0.9% Sodium Chloride, USP (containing 0.9% benzyl alcohol), which permits continuous intravenous infusion of blinatumomab at 28 mcg/day or 15 mcg/m²/day for a total of 7 days.

The 7-day infusion is not recommended for patients weighing less than 22 kg due to the risk of serious and sometimes fatal adverse events associated with benzyl alcohol in pediatric patients. See the full prescribing information for details.

The prescribing information for blinatumomab includes a boxed warning detailing the risk of cytokine release syndrome and neurologic toxicities. Blinatumomab is also under a Risk Evaluation and Mitigation Strategy program in the US intended to inform healthcare providers about these risks.

Blinatumomab is marketed by Amgen.

Trial results

With this sBLA, Amgen sought to make blinatumomab available as a treatment for patients with Ph+ relapsed/refractory BCP-ALL (as well as Ph-).

To this end, the application included data from the ALCANTARA study, which were published in the Journal of Clinical Oncology.

In this trial, researchers evaluated blinatumomab in adults with Ph+ relapsed/refractory BCP-ALL who had failed treatment with at least 1 tyrosine kinase inhibitor.

Thirty-six percent of patients achieved a complete response or complete response with partial hematologic recovery within the first 2 cycles of blinatumomab treatment. Of these patients, 88% were minimal residual disease-negative.

The most frequent adverse events (AEs) in this trial were pyrexia (58%), neurologic events (47%), febrile neutropenia (40%), and headache (31%). Three patients had grade 1/2 cytokine release syndrome, and 3 patients had grade 3 neurologic AEs.

The sBLA also included overall survival (OS) data from the phase 3 TOWER trial, which was intended to support the conversion of blinatumomab’s accelerated approval to a full approval.

Results from the TOWER trial were published in NEJM.

In this study, researchers compared blinatumomab to standard of care (SOC) chemotherapy (4 different regimens) in adults with Ph- relapsed/refractory BCP-ALL.

Blinatumomab produced higher response rates and nearly doubled OS compared to SOC. The median OS was 7.7 months in the blinatumomab arm and 4 months in the SOC arm. The hazard ratio for death was 0.71 (P=0.012).

The incidence of grade 3 or higher AEs was higher in the SOC arm, but the incidence of serious AEs was higher in the blinatumomab arm.

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has approved the supplemental biologics license application (sBLA) for blinatumomab (Blincyto®).

The aim of the sBLA was to expand the indication for blinatumomab to include all patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and to convert blinatumomab’s accelerated approval to a full approval.

Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

In 2014, the FDA granted blinatumomab accelerated approval to treat adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory BCP-ALL.

In 2016, the FDA granted the therapy accelerated approval for pediatric patients with Ph- relapsed/refractory BCP-ALL.

Now, the FDA has granted blinatumomab full approval for pediatric and adult patients with Ph- or Ph+ relapsed/refractory BCP-ALL.

The FDA also recently approved the sBLA for blinatumomab to be infused over 7 days with preservative, adding to the previously approved administration options for infusion over 24 and 48 hours (preservative-free).

The blinatumomab intravenous bag for a 7-day infusion contains Bacteriostatic 0.9% Sodium Chloride, USP (containing 0.9% benzyl alcohol), which permits continuous intravenous infusion of blinatumomab at 28 mcg/day or 15 mcg/m²/day for a total of 7 days.

The 7-day infusion is not recommended for patients weighing less than 22 kg due to the risk of serious and sometimes fatal adverse events associated with benzyl alcohol in pediatric patients. See the full prescribing information for details.

The prescribing information for blinatumomab includes a boxed warning detailing the risk of cytokine release syndrome and neurologic toxicities. Blinatumomab is also under a Risk Evaluation and Mitigation Strategy program in the US intended to inform healthcare providers about these risks.

Blinatumomab is marketed by Amgen.

Trial results

With this sBLA, Amgen sought to make blinatumomab available as a treatment for patients with Ph+ relapsed/refractory BCP-ALL (as well as Ph-).

To this end, the application included data from the ALCANTARA study, which were published in the Journal of Clinical Oncology.

In this trial, researchers evaluated blinatumomab in adults with Ph+ relapsed/refractory BCP-ALL who had failed treatment with at least 1 tyrosine kinase inhibitor.

Thirty-six percent of patients achieved a complete response or complete response with partial hematologic recovery within the first 2 cycles of blinatumomab treatment. Of these patients, 88% were minimal residual disease-negative.

The most frequent adverse events (AEs) in this trial were pyrexia (58%), neurologic events (47%), febrile neutropenia (40%), and headache (31%). Three patients had grade 1/2 cytokine release syndrome, and 3 patients had grade 3 neurologic AEs.

The sBLA also included overall survival (OS) data from the phase 3 TOWER trial, which was intended to support the conversion of blinatumomab’s accelerated approval to a full approval.

Results from the TOWER trial were published in NEJM.

In this study, researchers compared blinatumomab to standard of care (SOC) chemotherapy (4 different regimens) in adults with Ph- relapsed/refractory BCP-ALL.

Blinatumomab produced higher response rates and nearly doubled OS compared to SOC. The median OS was 7.7 months in the blinatumomab arm and 4 months in the SOC arm. The hazard ratio for death was 0.71 (P=0.012).

The incidence of grade 3 or higher AEs was higher in the SOC arm, but the incidence of serious AEs was higher in the blinatumomab arm.

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.