Patients with schizophrenia who have efficacy or tolerability concerns with paliperidone palmitate or risperidone long-acting injection can be switched safely to aripiprazole lauroxil, a small prospective, open-label study suggests.

“To our knowledge, this is the first prospective study of the safety of switching from other long-acting injectable antipsychotics to [aripiprazole lauroxil],” wrote Brian J. Miller, MD, and his associates.

The 6-month study included 51 patients (mean age, 40.6 years; 72.5% male) who were switched to aripiprazole lauroxil from either of the other long-acting injectables, reported Dr. Miller of Augusta University, Georgia, and his associates. They observed rates of discontinuation for any reason and discontinuation related to the new medication regimen. The study found that, at 6 months, all-cause discontinuation was 30.4% and medication-related discontinuation was 9.2% (Schizophr Res. 2019 Feb 7. doi: 10.1016/jschres.2019.01.38).

Statistically significant improvements were seen with aripiprazole lauroxil based on scores on the Clinical Global Impressions–Severity and the Brief Psychiatric Rating Scale. Safety was assessed by tracking adverse events; the observed adverse events were consistent with aripiprazole lauroxil’s known safety profile. Those improvements and tolerability seen with aripiprazole lauroxil are important, because the reasons for the switch had included experiencing residual symptoms or issues of tolerability with the previous treatment.

“The clinical benefit observed in the study occurred irrespective of the investigator-determined [aripiprazole lauroxil] dosing regimen, suggesting that clinicians have the flexibility to select the regimen that is most compatible with the individual needs of their patients,” the authors added.

The full report can be found in Schizophrenia Research.

[email protected]

Patients with schizophrenia who have efficacy or tolerability concerns with paliperidone palmitate or risperidone long-acting injection can be switched safely to aripiprazole lauroxil, a small prospective, open-label study suggests.

“To our knowledge, this is the first prospective study of the safety of switching from other long-acting injectable antipsychotics to [aripiprazole lauroxil],” wrote Brian J. Miller, MD, and his associates.

The 6-month study included 51 patients (mean age, 40.6 years; 72.5% male) who were switched to aripiprazole lauroxil from either of the other long-acting injectables, reported Dr. Miller of Augusta University, Georgia, and his associates. They observed rates of discontinuation for any reason and discontinuation related to the new medication regimen. The study found that, at 6 months, all-cause discontinuation was 30.4% and medication-related discontinuation was 9.2% (Schizophr Res. 2019 Feb 7. doi: 10.1016/jschres.2019.01.38).

Statistically significant improvements were seen with aripiprazole lauroxil based on scores on the Clinical Global Impressions–Severity and the Brief Psychiatric Rating Scale. Safety was assessed by tracking adverse events; the observed adverse events were consistent with aripiprazole lauroxil’s known safety profile. Those improvements and tolerability seen with aripiprazole lauroxil are important, because the reasons for the switch had included experiencing residual symptoms or issues of tolerability with the previous treatment.

“The clinical benefit observed in the study occurred irrespective of the investigator-determined [aripiprazole lauroxil] dosing regimen, suggesting that clinicians have the flexibility to select the regimen that is most compatible with the individual needs of their patients,” the authors added.

The full report can be found in Schizophrenia Research.

[email protected]

Patients with schizophrenia who have efficacy or tolerability concerns with paliperidone palmitate or risperidone long-acting injection can be switched safely to aripiprazole lauroxil, a small prospective, open-label study suggests.

“To our knowledge, this is the first prospective study of the safety of switching from other long-acting injectable antipsychotics to [aripiprazole lauroxil],” wrote Brian J. Miller, MD, and his associates.

The 6-month study included 51 patients (mean age, 40.6 years; 72.5% male) who were switched to aripiprazole lauroxil from either of the other long-acting injectables, reported Dr. Miller of Augusta University, Georgia, and his associates. They observed rates of discontinuation for any reason and discontinuation related to the new medication regimen. The study found that, at 6 months, all-cause discontinuation was 30.4% and medication-related discontinuation was 9.2% (Schizophr Res. 2019 Feb 7. doi: 10.1016/jschres.2019.01.38).

Statistically significant improvements were seen with aripiprazole lauroxil based on scores on the Clinical Global Impressions–Severity and the Brief Psychiatric Rating Scale. Safety was assessed by tracking adverse events; the observed adverse events were consistent with aripiprazole lauroxil’s known safety profile. Those improvements and tolerability seen with aripiprazole lauroxil are important, because the reasons for the switch had included experiencing residual symptoms or issues of tolerability with the previous treatment.

“The clinical benefit observed in the study occurred irrespective of the investigator-determined [aripiprazole lauroxil] dosing regimen, suggesting that clinicians have the flexibility to select the regimen that is most compatible with the individual needs of their patients,” the authors added.

The full report can be found in Schizophrenia Research.

[email protected]

The European Commission (EC) has approved brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) to treat adults with previously untreated, CD30+, stage IV Hodgkin lymphoma (HL).

This is the fifth approved indication for BV (Adcetris) in Europe. The drug is already EC approved to treat adults with CD30+ HL at increased risk of relapse or progression after autologous stem cell transplant (ASCT); relapsed or refractory, CD30+ HL after ASCT or at least two prior therapies when ASCT or multi-agent chemotherapy is not an option; relapsed or refractory systemic anaplastic large-cell lymphoma; and CD30+ cutaneous T-cell lymphoma after at least one prior systemic therapy.

The EC’s approval of BV plus AVD is supported by the phase 3 ECHELON-1 trial (N Engl J Med. 2018;378:331-44).

ECHELON-1 included 1,334 patients with advanced HL who received BV plus AVD (n = 664) or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD, n = 670) as frontline treatment.

The study's primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review committee, BV plus AVD provided a significant improvement in modified PFS. The 2-year modified PFS rate was 82% in the BV-AVD arm and 77% in the ABVD arm (hazard ratio = 0.77; P = .04).

There was no significant difference between the treatment arms in response rates or overall survival.

The overall incidence of adverse events (AEs) was 99% in the BV-AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively. The incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with BV-AVD, while pulmonary toxicity was more common with ABVD.

The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals (a Takeda company) in collaboration with Seattle Genetics.

[email protected]

The European Commission (EC) has approved brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) to treat adults with previously untreated, CD30+, stage IV Hodgkin lymphoma (HL).

This is the fifth approved indication for BV (Adcetris) in Europe. The drug is already EC approved to treat adults with CD30+ HL at increased risk of relapse or progression after autologous stem cell transplant (ASCT); relapsed or refractory, CD30+ HL after ASCT or at least two prior therapies when ASCT or multi-agent chemotherapy is not an option; relapsed or refractory systemic anaplastic large-cell lymphoma; and CD30+ cutaneous T-cell lymphoma after at least one prior systemic therapy.

The EC’s approval of BV plus AVD is supported by the phase 3 ECHELON-1 trial (N Engl J Med. 2018;378:331-44).

ECHELON-1 included 1,334 patients with advanced HL who received BV plus AVD (n = 664) or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD, n = 670) as frontline treatment.

The study's primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review committee, BV plus AVD provided a significant improvement in modified PFS. The 2-year modified PFS rate was 82% in the BV-AVD arm and 77% in the ABVD arm (hazard ratio = 0.77; P = .04).

There was no significant difference between the treatment arms in response rates or overall survival.

The overall incidence of adverse events (AEs) was 99% in the BV-AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively. The incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with BV-AVD, while pulmonary toxicity was more common with ABVD.

The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals (a Takeda company) in collaboration with Seattle Genetics.

[email protected]

The European Commission (EC) has approved brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) to treat adults with previously untreated, CD30+, stage IV Hodgkin lymphoma (HL).

This is the fifth approved indication for BV (Adcetris) in Europe. The drug is already EC approved to treat adults with CD30+ HL at increased risk of relapse or progression after autologous stem cell transplant (ASCT); relapsed or refractory, CD30+ HL after ASCT or at least two prior therapies when ASCT or multi-agent chemotherapy is not an option; relapsed or refractory systemic anaplastic large-cell lymphoma; and CD30+ cutaneous T-cell lymphoma after at least one prior systemic therapy.

The EC’s approval of BV plus AVD is supported by the phase 3 ECHELON-1 trial (N Engl J Med. 2018;378:331-44).

ECHELON-1 included 1,334 patients with advanced HL who received BV plus AVD (n = 664) or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD, n = 670) as frontline treatment.

The study's primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review committee, BV plus AVD provided a significant improvement in modified PFS. The 2-year modified PFS rate was 82% in the BV-AVD arm and 77% in the ABVD arm (hazard ratio = 0.77; P = .04).

There was no significant difference between the treatment arms in response rates or overall survival.

The overall incidence of adverse events (AEs) was 99% in the BV-AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively. The incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with BV-AVD, while pulmonary toxicity was more common with ABVD.

The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals (a Takeda company) in collaboration with Seattle Genetics.

[email protected]

FDA panels are backing intranasal esketamine for refractory depression. Also today, the office of the National Coordinator of Health Information Technology aims to help doctors and patients with information sharing, most physicians think that health care costs and access are unlikely to improve in 2019, and vaccination and antiviral treatment do not affect the risk of stroke following shingles.
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FDA panels are backing intranasal esketamine for refractory depression. Also today, the office of the National Coordinator of Health Information Technology aims to help doctors and patients with information sharing, most physicians think that health care costs and access are unlikely to improve in 2019, and vaccination and antiviral treatment do not affect the risk of stroke following shingles.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

FDA panels are backing intranasal esketamine for refractory depression. Also today, the office of the National Coordinator of Health Information Technology aims to help doctors and patients with information sharing, most physicians think that health care costs and access are unlikely to improve in 2019, and vaccination and antiviral treatment do not affect the risk of stroke following shingles.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

Children referred for mental health services in Los Angeles County using a telehealth referral were three times more likely to complete a community mental health clinic (CMHC) screening than children receiving conventional mental health referrals, a study found.

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“Our findings highlight the importance of this initial access point for a successful referral to the CHMC,” Tumaini R. Coker, MD, MBA, of the University of Washington, Seattle, and Seattle Children’s Research Institute, and her colleagues wrote in Pediatrics. “We can hypothesize that the assistance from the telehealth care coordinator may have played an important role in access for families.”

Although this study was not powered to compare psychological health or quality-of-life differences, a larger study with a longer follow-up period may allow study of “variation in health outcomes … among a sample of all who were initially referred, particularly if the higher rates of access for children in the intervention translate into a greater proportion of children receiving services,” the authors wrote.

The research group partnered with two community mental health clinics (CMHCs) and six federally qualified health center clinics, the latter randomly assigned as control or intervention. The telehealth-enhanced referral process developed by the researchers involved patients at the intervention clinics viewing a video orientation to the CMHC and then participating in a live video conference for screening. Completion of the referral screening visit was the measure for CMHC access as a primary endpoint.

Among the 342 children, aged 5-12 years (average, 9 years), enrolled in the study, 87% were Latino, and 62% were boys.

Of children using the telehealth referral process, 80% completed an initial CMHC screening, compared to 64% of children receiving referrals via usual care procedures, resulting in three-times greater odds of a screening in the intervention group (adjusted odds ratio, 3.02).

It took approximately 6 more days for the telehealth-referred children to complete the screening.

“The increased time to the initial access point was anticipated for the intervention clinics because the telehealth care coordinator and CMHC staff held all the videoconference screening visits on a single preselected day each week,” which thereby limited availability of slots for screenings, Dr. Coker and her associates wrote.

Children who received telehealth-enabled referrals reported higher satisfaction levels with the referral system and with care, compared with those using usual care methods. Of the 342 children in the study, 213 were considered eligible to receive CMHC services. Reasons for ineligibility for services included presence of a developmental disability, lack of an mental health need, private health insurance coverage, a zip code outside of the CMHC’s catchment area, and not meeting income requirements.

Of those 213, 80% of the intervention group and 84% of controls subsequently had a mental health visit.

A study limitation is its personalization to the community partners involved, which may require different procedures in other settings, the authors noted. The study also did not look at the quality of mental health services received after initial screenings, precluding the ability to assess clinical outcomes. In addition, “the CMHCs did not involve the payers of mental health care for this population, limiting our capacity to identify barriers and system solutions that may improve the intervention’s sustainability,” the authors wrote.

The research was funded by grants from the Patient-Centered Outcomes Research Institute and the California Community Foundation. The authors reported having no relevant financial disclosures.

SOURCE: Coker TR et al. Pediatrics. 2019 Feb 15. doi: 10.1542/peds.2018-2738.

Children referred for mental health services in Los Angeles County using a telehealth referral were three times more likely to complete a community mental health clinic (CMHC) screening than children receiving conventional mental health referrals, a study found.

Getty Images

“Our findings highlight the importance of this initial access point for a successful referral to the CHMC,” Tumaini R. Coker, MD, MBA, of the University of Washington, Seattle, and Seattle Children’s Research Institute, and her colleagues wrote in Pediatrics. “We can hypothesize that the assistance from the telehealth care coordinator may have played an important role in access for families.”

Although this study was not powered to compare psychological health or quality-of-life differences, a larger study with a longer follow-up period may allow study of “variation in health outcomes … among a sample of all who were initially referred, particularly if the higher rates of access for children in the intervention translate into a greater proportion of children receiving services,” the authors wrote.

The research group partnered with two community mental health clinics (CMHCs) and six federally qualified health center clinics, the latter randomly assigned as control or intervention. The telehealth-enhanced referral process developed by the researchers involved patients at the intervention clinics viewing a video orientation to the CMHC and then participating in a live video conference for screening. Completion of the referral screening visit was the measure for CMHC access as a primary endpoint.

Among the 342 children, aged 5-12 years (average, 9 years), enrolled in the study, 87% were Latino, and 62% were boys.

Of children using the telehealth referral process, 80% completed an initial CMHC screening, compared to 64% of children receiving referrals via usual care procedures, resulting in three-times greater odds of a screening in the intervention group (adjusted odds ratio, 3.02).

It took approximately 6 more days for the telehealth-referred children to complete the screening.

“The increased time to the initial access point was anticipated for the intervention clinics because the telehealth care coordinator and CMHC staff held all the videoconference screening visits on a single preselected day each week,” which thereby limited availability of slots for screenings, Dr. Coker and her associates wrote.

Children who received telehealth-enabled referrals reported higher satisfaction levels with the referral system and with care, compared with those using usual care methods. Of the 342 children in the study, 213 were considered eligible to receive CMHC services. Reasons for ineligibility for services included presence of a developmental disability, lack of an mental health need, private health insurance coverage, a zip code outside of the CMHC’s catchment area, and not meeting income requirements.

Of those 213, 80% of the intervention group and 84% of controls subsequently had a mental health visit.

A study limitation is its personalization to the community partners involved, which may require different procedures in other settings, the authors noted. The study also did not look at the quality of mental health services received after initial screenings, precluding the ability to assess clinical outcomes. In addition, “the CMHCs did not involve the payers of mental health care for this population, limiting our capacity to identify barriers and system solutions that may improve the intervention’s sustainability,” the authors wrote.

The research was funded by grants from the Patient-Centered Outcomes Research Institute and the California Community Foundation. The authors reported having no relevant financial disclosures.

SOURCE: Coker TR et al. Pediatrics. 2019 Feb 15. doi: 10.1542/peds.2018-2738.

Children referred for mental health services in Los Angeles County using a telehealth referral were three times more likely to complete a community mental health clinic (CMHC) screening than children receiving conventional mental health referrals, a study found.

Getty Images

“Our findings highlight the importance of this initial access point for a successful referral to the CHMC,” Tumaini R. Coker, MD, MBA, of the University of Washington, Seattle, and Seattle Children’s Research Institute, and her colleagues wrote in Pediatrics. “We can hypothesize that the assistance from the telehealth care coordinator may have played an important role in access for families.”

Although this study was not powered to compare psychological health or quality-of-life differences, a larger study with a longer follow-up period may allow study of “variation in health outcomes … among a sample of all who were initially referred, particularly if the higher rates of access for children in the intervention translate into a greater proportion of children receiving services,” the authors wrote.

The research group partnered with two community mental health clinics (CMHCs) and six federally qualified health center clinics, the latter randomly assigned as control or intervention. The telehealth-enhanced referral process developed by the researchers involved patients at the intervention clinics viewing a video orientation to the CMHC and then participating in a live video conference for screening. Completion of the referral screening visit was the measure for CMHC access as a primary endpoint.

Among the 342 children, aged 5-12 years (average, 9 years), enrolled in the study, 87% were Latino, and 62% were boys.

Of children using the telehealth referral process, 80% completed an initial CMHC screening, compared to 64% of children receiving referrals via usual care procedures, resulting in three-times greater odds of a screening in the intervention group (adjusted odds ratio, 3.02).

It took approximately 6 more days for the telehealth-referred children to complete the screening.

“The increased time to the initial access point was anticipated for the intervention clinics because the telehealth care coordinator and CMHC staff held all the videoconference screening visits on a single preselected day each week,” which thereby limited availability of slots for screenings, Dr. Coker and her associates wrote.

Children who received telehealth-enabled referrals reported higher satisfaction levels with the referral system and with care, compared with those using usual care methods. Of the 342 children in the study, 213 were considered eligible to receive CMHC services. Reasons for ineligibility for services included presence of a developmental disability, lack of an mental health need, private health insurance coverage, a zip code outside of the CMHC’s catchment area, and not meeting income requirements.

Of those 213, 80% of the intervention group and 84% of controls subsequently had a mental health visit.

A study limitation is its personalization to the community partners involved, which may require different procedures in other settings, the authors noted. The study also did not look at the quality of mental health services received after initial screenings, precluding the ability to assess clinical outcomes. In addition, “the CMHCs did not involve the payers of mental health care for this population, limiting our capacity to identify barriers and system solutions that may improve the intervention’s sustainability,” the authors wrote.

The research was funded by grants from the Patient-Centered Outcomes Research Institute and the California Community Foundation. The authors reported having no relevant financial disclosures.

SOURCE: Coker TR et al. Pediatrics. 2019 Feb 15. doi: 10.1542/peds.2018-2738.

A 45-year-old woman is referred to dermatology for a “fungal infection” that has failed to respond to the following treatments: topical clotrimazole cream, topical miconazole cream, a 30-day course of oral terbinafine (250 mg/d), and a 2-month course of oral griseofulvin (unknown dose). The lesions are completely asymptomatic but quite worrisome to the patient since they manifested 6 months ago.

She has consulted at least 6 different providers—none of whom was a dermatologist but all of whom were certain of the diagnosis and thus felt no need to refer the patient. However, the passage of time and trail of ineffective treatments finally prompts the (albeit reluctant) decision to send the patient to dermatology.

On questioning, she denies any serious health problems, such as diabetes or immunosuppression. She has had no contact with any animals or children.

EXAMINATION
The lesions in question total 6; all are uniformly purplish brown, round, and macular, and they range from 5 mm to more than 3 cm. Most are located on the bilateral popliteal areas. The lesions have sharp, well-defined margins. Several have faintly raised papular margins that give the centers a slightly concave appearance.

Palpation reveals the complete absence of any surface disturbance, such as scaling or erosion. Thus, no KOH prep can be performed to check for fungal elements. Instead, a shave biopsy is performed, the results of which show a sawtooth-patterned lymphocytic infiltrate obliterating the normally smooth undulating dermoepidermal junction.

What’s the diagnosis?

DISCUSSION
This case effectively demonstrates the principle that, when confronted with round or annular lesions, some providers will rely on the diagnosis of “fungal” even when evidence (eg, failed treatment attempts) suggests otherwise. What that nonresponse should do is signal the need for an expanded differential—that is, a consideration of other diagnostic possibilities. This is a bedrock principle in every medical specialty, not just in dermatology.

In this case, the biopsy results clearly pointed to the correct diagnosis of lichen planus (LP), a common dermatosis well known to present in annular morphology. LP is a benign process, albeit one that is occasionally quite bothersome (eg, itching) and, rarely, widespread. LP’s more typical distribution is on volar wrists, in the sacral areas, and occasionally on genitals, so the inability to make a visual diagnosis in this case is forgivable.

Although LP’s etiology is unfortunately unknown, what is known is how to treat it: with topical steroids when necessary or “tincture of time,” as in this patient’s asymptomatic case. LP typically resolves on its own, and it has no worrisome import or connections to more serious disease.

But as always, the first step to correct diagnosis is to consider letting go of the old diagnosis—fungal infection—which was clearly incorrect given the lack of response to numerous antifungals. The second step is to consider other possibilities, which would include lichen planus, psoriasis, granuloma annulare, tinea versicolor, and necrobiosis. The third step is to perform a biopsy, which would establish the correct diagnosis with certainty and in turn, dictate correct treatment.

TAKE-HOME LEARNING POINTS

• There is an extensive differential for round or annular skin lesions that includes many nonfungal causes.
• When antifungals fail to help, consider other diagnostic possibilities.
• Perform a biopsy when a visual diagnosis is not possible.
• Lichen planus (LP) is a common benign inflammatory skin condition that can present with annular lesions.

A 45-year-old woman is referred to dermatology for a “fungal infection” that has failed to respond to the following treatments: topical clotrimazole cream, topical miconazole cream, a 30-day course of oral terbinafine (250 mg/d), and a 2-month course of oral griseofulvin (unknown dose). The lesions are completely asymptomatic but quite worrisome to the patient since they manifested 6 months ago.

She has consulted at least 6 different providers—none of whom was a dermatologist but all of whom were certain of the diagnosis and thus felt no need to refer the patient. However, the passage of time and trail of ineffective treatments finally prompts the (albeit reluctant) decision to send the patient to dermatology.

On questioning, she denies any serious health problems, such as diabetes or immunosuppression. She has had no contact with any animals or children.

EXAMINATION
The lesions in question total 6; all are uniformly purplish brown, round, and macular, and they range from 5 mm to more than 3 cm. Most are located on the bilateral popliteal areas. The lesions have sharp, well-defined margins. Several have faintly raised papular margins that give the centers a slightly concave appearance.

Palpation reveals the complete absence of any surface disturbance, such as scaling or erosion. Thus, no KOH prep can be performed to check for fungal elements. Instead, a shave biopsy is performed, the results of which show a sawtooth-patterned lymphocytic infiltrate obliterating the normally smooth undulating dermoepidermal junction.

What’s the diagnosis?

DISCUSSION
This case effectively demonstrates the principle that, when confronted with round or annular lesions, some providers will rely on the diagnosis of “fungal” even when evidence (eg, failed treatment attempts) suggests otherwise. What that nonresponse should do is signal the need for an expanded differential—that is, a consideration of other diagnostic possibilities. This is a bedrock principle in every medical specialty, not just in dermatology.

In this case, the biopsy results clearly pointed to the correct diagnosis of lichen planus (LP), a common dermatosis well known to present in annular morphology. LP is a benign process, albeit one that is occasionally quite bothersome (eg, itching) and, rarely, widespread. LP’s more typical distribution is on volar wrists, in the sacral areas, and occasionally on genitals, so the inability to make a visual diagnosis in this case is forgivable.

Although LP’s etiology is unfortunately unknown, what is known is how to treat it: with topical steroids when necessary or “tincture of time,” as in this patient’s asymptomatic case. LP typically resolves on its own, and it has no worrisome import or connections to more serious disease.

But as always, the first step to correct diagnosis is to consider letting go of the old diagnosis—fungal infection—which was clearly incorrect given the lack of response to numerous antifungals. The second step is to consider other possibilities, which would include lichen planus, psoriasis, granuloma annulare, tinea versicolor, and necrobiosis. The third step is to perform a biopsy, which would establish the correct diagnosis with certainty and in turn, dictate correct treatment.

TAKE-HOME LEARNING POINTS

• There is an extensive differential for round or annular skin lesions that includes many nonfungal causes.
• When antifungals fail to help, consider other diagnostic possibilities.
• Perform a biopsy when a visual diagnosis is not possible.
• Lichen planus (LP) is a common benign inflammatory skin condition that can present with annular lesions.

A 45-year-old woman is referred to dermatology for a “fungal infection” that has failed to respond to the following treatments: topical clotrimazole cream, topical miconazole cream, a 30-day course of oral terbinafine (250 mg/d), and a 2-month course of oral griseofulvin (unknown dose). The lesions are completely asymptomatic but quite worrisome to the patient since they manifested 6 months ago.

She has consulted at least 6 different providers—none of whom was a dermatologist but all of whom were certain of the diagnosis and thus felt no need to refer the patient. However, the passage of time and trail of ineffective treatments finally prompts the (albeit reluctant) decision to send the patient to dermatology.

On questioning, she denies any serious health problems, such as diabetes or immunosuppression. She has had no contact with any animals or children.

EXAMINATION
The lesions in question total 6; all are uniformly purplish brown, round, and macular, and they range from 5 mm to more than 3 cm. Most are located on the bilateral popliteal areas. The lesions have sharp, well-defined margins. Several have faintly raised papular margins that give the centers a slightly concave appearance.

Palpation reveals the complete absence of any surface disturbance, such as scaling or erosion. Thus, no KOH prep can be performed to check for fungal elements. Instead, a shave biopsy is performed, the results of which show a sawtooth-patterned lymphocytic infiltrate obliterating the normally smooth undulating dermoepidermal junction.

What’s the diagnosis?

DISCUSSION
This case effectively demonstrates the principle that, when confronted with round or annular lesions, some providers will rely on the diagnosis of “fungal” even when evidence (eg, failed treatment attempts) suggests otherwise. What that nonresponse should do is signal the need for an expanded differential—that is, a consideration of other diagnostic possibilities. This is a bedrock principle in every medical specialty, not just in dermatology.

In this case, the biopsy results clearly pointed to the correct diagnosis of lichen planus (LP), a common dermatosis well known to present in annular morphology. LP is a benign process, albeit one that is occasionally quite bothersome (eg, itching) and, rarely, widespread. LP’s more typical distribution is on volar wrists, in the sacral areas, and occasionally on genitals, so the inability to make a visual diagnosis in this case is forgivable.

Although LP’s etiology is unfortunately unknown, what is known is how to treat it: with topical steroids when necessary or “tincture of time,” as in this patient’s asymptomatic case. LP typically resolves on its own, and it has no worrisome import or connections to more serious disease.

But as always, the first step to correct diagnosis is to consider letting go of the old diagnosis—fungal infection—which was clearly incorrect given the lack of response to numerous antifungals. The second step is to consider other possibilities, which would include lichen planus, psoriasis, granuloma annulare, tinea versicolor, and necrobiosis. The third step is to perform a biopsy, which would establish the correct diagnosis with certainty and in turn, dictate correct treatment.

TAKE-HOME LEARNING POINTS

• There is an extensive differential for round or annular skin lesions that includes many nonfungal causes.
• When antifungals fail to help, consider other diagnostic possibilities.
• Perform a biopsy when a visual diagnosis is not possible.
• Lichen planus (LP) is a common benign inflammatory skin condition that can present with annular lesions.

Patient-reported outcomes should be the priority consideration for determining whether the three synthetic mesh devices currently available for transvaginal repair of pelvic organ prolapse (POP) in the anterior vaginal compartment should remain on the market, according to the Food and Drug Administration Obstetrics and Gynecology Devices panel.

The panel was convened in February 2019 to advise the Food and Drug Administration on how it should evaluate the safety and effectiveness of the three currently marketed devices – each of which has ongoing postmarket surveillance studies – as well as any other similar devices that come up for premarket approval in the future.

The panel’s main messages: Subjective outcomes are what really matter – even more so than anatomic or objective outcomes – as does long-term follow-up.

“The panel generally believes that both anatomic/objective and subjective outcomes should be used” to assess the effectiveness of mesh repair, “compared to native tissue repair,” said panel chair Keith Isaacson, MD, medical director of the Newton-Wellesley Hospital in Newton, Mass. “But we feel that, if we had to score [each category of outcome], about 75% should be subjective.”

The three devices currently marketed for transvaginal repair of POP (Boston Scientific’s Uphold LITE and Xenform, as well as Coloplast’s Restorelle DirectFix Anterior) are being scrutinized under a new regulatory paradigm and amid a charged backdrop of safety warnings and years of lawsuits regarding debilitating complications following surgeries that involved the implantation of synthetic vaginal mesh.

The two manufacturers of the currently available devices launched postmarket surveillance studies, called 522 studies, after the FDA issued postmarket surveillance study orders in 2012 to all manufacturers of surgical mesh for transvaginal repair of POP. (Most companies chose at the time to pull their products from the market.) This FDA action, along with a reclassification of the devices from class II to the high-risk class III, had been recommended at a 2011 meeting of the Obstetrics and Gynecology Devices panel.

In anticipation of a future reclassification, the 522 studies were designed at the time to support future premarket approval (PMA) applications, as advised by the FDA. Now, as a result of the 2016 reclassification of surgical mesh for transvaginal POP repair to class III – and the companies’ subsequent PMA applications – the FDA is reviewing the ongoing postmarket study results with a PMA lens to determine each device’s benefit/risk profile.

It’s a challenging assessment to make, FDA officials said.

The agency reported to the panel that a search of medical device reports from 2008 to 2018 identified 11,274 adverse events associated with mesh placed in the anterior vaginal compartment to treat POP. These included 10,391 reports of serious injury, 806 reports of device malfunctions, and 77 reports of death.

Patient-reported outcomes should be the priority consideration for determining whether the three synthetic mesh devices currently available for transvaginal repair of pelvic organ prolapse (POP) in the anterior vaginal compartment should remain on the market, according to the Food and Drug Administration Obstetrics and Gynecology Devices panel.

The panel was convened in February 2019 to advise the Food and Drug Administration on how it should evaluate the safety and effectiveness of the three currently marketed devices – each of which has ongoing postmarket surveillance studies – as well as any other similar devices that come up for premarket approval in the future.

The panel’s main messages: Subjective outcomes are what really matter – even more so than anatomic or objective outcomes – as does long-term follow-up.

“The panel generally believes that both anatomic/objective and subjective outcomes should be used” to assess the effectiveness of mesh repair, “compared to native tissue repair,” said panel chair Keith Isaacson, MD, medical director of the Newton-Wellesley Hospital in Newton, Mass. “But we feel that, if we had to score [each category of outcome], about 75% should be subjective.”

The three devices currently marketed for transvaginal repair of POP (Boston Scientific’s Uphold LITE and Xenform, as well as Coloplast’s Restorelle DirectFix Anterior) are being scrutinized under a new regulatory paradigm and amid a charged backdrop of safety warnings and years of lawsuits regarding debilitating complications following surgeries that involved the implantation of synthetic vaginal mesh.

The two manufacturers of the currently available devices launched postmarket surveillance studies, called 522 studies, after the FDA issued postmarket surveillance study orders in 2012 to all manufacturers of surgical mesh for transvaginal repair of POP. (Most companies chose at the time to pull their products from the market.) This FDA action, along with a reclassification of the devices from class II to the high-risk class III, had been recommended at a 2011 meeting of the Obstetrics and Gynecology Devices panel.

In anticipation of a future reclassification, the 522 studies were designed at the time to support future premarket approval (PMA) applications, as advised by the FDA. Now, as a result of the 2016 reclassification of surgical mesh for transvaginal POP repair to class III – and the companies’ subsequent PMA applications – the FDA is reviewing the ongoing postmarket study results with a PMA lens to determine each device’s benefit/risk profile.

It’s a challenging assessment to make, FDA officials said.

The agency reported to the panel that a search of medical device reports from 2008 to 2018 identified 11,274 adverse events associated with mesh placed in the anterior vaginal compartment to treat POP. These included 10,391 reports of serious injury, 806 reports of device malfunctions, and 77 reports of death.

Patient-reported outcomes should be the priority consideration for determining whether the three synthetic mesh devices currently available for transvaginal repair of pelvic organ prolapse (POP) in the anterior vaginal compartment should remain on the market, according to the Food and Drug Administration Obstetrics and Gynecology Devices panel.

The panel was convened in February 2019 to advise the Food and Drug Administration on how it should evaluate the safety and effectiveness of the three currently marketed devices – each of which has ongoing postmarket surveillance studies – as well as any other similar devices that come up for premarket approval in the future.

The panel’s main messages: Subjective outcomes are what really matter – even more so than anatomic or objective outcomes – as does long-term follow-up.

“The panel generally believes that both anatomic/objective and subjective outcomes should be used” to assess the effectiveness of mesh repair, “compared to native tissue repair,” said panel chair Keith Isaacson, MD, medical director of the Newton-Wellesley Hospital in Newton, Mass. “But we feel that, if we had to score [each category of outcome], about 75% should be subjective.”

The three devices currently marketed for transvaginal repair of POP (Boston Scientific’s Uphold LITE and Xenform, as well as Coloplast’s Restorelle DirectFix Anterior) are being scrutinized under a new regulatory paradigm and amid a charged backdrop of safety warnings and years of lawsuits regarding debilitating complications following surgeries that involved the implantation of synthetic vaginal mesh.

The two manufacturers of the currently available devices launched postmarket surveillance studies, called 522 studies, after the FDA issued postmarket surveillance study orders in 2012 to all manufacturers of surgical mesh for transvaginal repair of POP. (Most companies chose at the time to pull their products from the market.) This FDA action, along with a reclassification of the devices from class II to the high-risk class III, had been recommended at a 2011 meeting of the Obstetrics and Gynecology Devices panel.

In anticipation of a future reclassification, the 522 studies were designed at the time to support future premarket approval (PMA) applications, as advised by the FDA. Now, as a result of the 2016 reclassification of surgical mesh for transvaginal POP repair to class III – and the companies’ subsequent PMA applications – the FDA is reviewing the ongoing postmarket study results with a PMA lens to determine each device’s benefit/risk profile.

It’s a challenging assessment to make, FDA officials said.

The agency reported to the panel that a search of medical device reports from 2008 to 2018 identified 11,274 adverse events associated with mesh placed in the anterior vaginal compartment to treat POP. These included 10,391 reports of serious injury, 806 reports of device malfunctions, and 77 reports of death.

PRAGUE – Fitusiran, a novel small interfering RNA therapeutic that decreases antithrombin (AT) synthesis and bleeding in patients with hemophilia A or B, with or without inhibitors, is reversible upon dosing cessation and becomes effective again with resumption of dosing. That finding is based on data obtained before, during, and after a phase 2 study dosing suspension.

Will Pass/MDedge News

In September 2017, the fitusiran open-label extension study was suspended to investigate a fatal thrombotic event. The suspension was lifted 3 months later, and the trial continued with reduced doses of replacement factors or bypassing agents for breakthrough bleeds.

The pause in the study was used to gather data about the effects of dosing cessation and resumption, which were reported by coauthor Craig Benson, MD, of Sanofi Genzyme in Cambridge, Mass. Dr. Benson presented findings at the annual congress of the European Association for Haemophilia and Allied Disorders on behalf of lead author John Pasi, MD, PhD, of the Haemophilia Centre at the Royal London Hospital and colleagues.

Prior to the suspension, 28 patients with hemophilia A or B, with or without inhibitors, were given 50-80 mg of fitusiran for up to 20 months with a median dose duration of 11 months. During dosing suspension, the investigators measured AT levels, thrombin generation, and annualized bleeding rates (ABR).

“We can see that the antithrombin knockdown effect of fitusiran is reversible with dosing hold,” Dr. Benson said, referring to an upward trend of median AT level.

Within 4 months of stopping fitusiran, median AT level was 60% of normal. This level continued to rise to about 90% by month 7, before returning to normal at month 11.

“This is an AT recovery we had previously seen by a few subjects that had discontinued [fitusiran] prior to the clinical hold,” Dr. Benson said, “but here, with a much larger sample size, we see a fairly consistent AT recovery.”

As expected, while AT levels rose, thrombin generation showed an inverse trend. “We see a similar temporal pattern,” Dr. Benson said. “The bulk of thrombin generation decrease is seen by the 4th month off fitusiran.”

When patients restarted fitusiran after the suspension was lifted, AT levels dropped to about 30% of normal by month 1 and about 20% of normal from month 2 onward. Again, in an inverse manner, thrombin generation increased.

Clinically, changes in AT and thrombin generation before, during, and after study suspension were reflected in median ABR, which rose from 1.43 events per year prior to cessation to 6.47 events per year during treatment hold before falling to 1.25 events per year after restarting fitusiran.

Overall, the results support the efficacy and reversibility of fitusiran. The agent is continuing to be studied in the phase 3 ATLAS trials.

The study was funded by Sanofi Genzyme and Alnylam. Dr. Benson is an employee of Sanofi Genzyme. Other investigators reported financial ties to Sanofi Genzyme, Alnylam, Baxalta, Octapharma, Pfizer, Shire, and others.

SOURCE: Pasi J et al. EAHAD 2019, Abstract OR16.

PRAGUE – Fitusiran, a novel small interfering RNA therapeutic that decreases antithrombin (AT) synthesis and bleeding in patients with hemophilia A or B, with or without inhibitors, is reversible upon dosing cessation and becomes effective again with resumption of dosing. That finding is based on data obtained before, during, and after a phase 2 study dosing suspension.

Will Pass/MDedge News

In September 2017, the fitusiran open-label extension study was suspended to investigate a fatal thrombotic event. The suspension was lifted 3 months later, and the trial continued with reduced doses of replacement factors or bypassing agents for breakthrough bleeds.

The pause in the study was used to gather data about the effects of dosing cessation and resumption, which were reported by coauthor Craig Benson, MD, of Sanofi Genzyme in Cambridge, Mass. Dr. Benson presented findings at the annual congress of the European Association for Haemophilia and Allied Disorders on behalf of lead author John Pasi, MD, PhD, of the Haemophilia Centre at the Royal London Hospital and colleagues.

Prior to the suspension, 28 patients with hemophilia A or B, with or without inhibitors, were given 50-80 mg of fitusiran for up to 20 months with a median dose duration of 11 months. During dosing suspension, the investigators measured AT levels, thrombin generation, and annualized bleeding rates (ABR).

“We can see that the antithrombin knockdown effect of fitusiran is reversible with dosing hold,” Dr. Benson said, referring to an upward trend of median AT level.

Within 4 months of stopping fitusiran, median AT level was 60% of normal. This level continued to rise to about 90% by month 7, before returning to normal at month 11.

“This is an AT recovery we had previously seen by a few subjects that had discontinued [fitusiran] prior to the clinical hold,” Dr. Benson said, “but here, with a much larger sample size, we see a fairly consistent AT recovery.”

As expected, while AT levels rose, thrombin generation showed an inverse trend. “We see a similar temporal pattern,” Dr. Benson said. “The bulk of thrombin generation decrease is seen by the 4th month off fitusiran.”

When patients restarted fitusiran after the suspension was lifted, AT levels dropped to about 30% of normal by month 1 and about 20% of normal from month 2 onward. Again, in an inverse manner, thrombin generation increased.

Clinically, changes in AT and thrombin generation before, during, and after study suspension were reflected in median ABR, which rose from 1.43 events per year prior to cessation to 6.47 events per year during treatment hold before falling to 1.25 events per year after restarting fitusiran.

Overall, the results support the efficacy and reversibility of fitusiran. The agent is continuing to be studied in the phase 3 ATLAS trials.

The study was funded by Sanofi Genzyme and Alnylam. Dr. Benson is an employee of Sanofi Genzyme. Other investigators reported financial ties to Sanofi Genzyme, Alnylam, Baxalta, Octapharma, Pfizer, Shire, and others.

SOURCE: Pasi J et al. EAHAD 2019, Abstract OR16.

PRAGUE – Fitusiran, a novel small interfering RNA therapeutic that decreases antithrombin (AT) synthesis and bleeding in patients with hemophilia A or B, with or without inhibitors, is reversible upon dosing cessation and becomes effective again with resumption of dosing. That finding is based on data obtained before, during, and after a phase 2 study dosing suspension.

Will Pass/MDedge News

In September 2017, the fitusiran open-label extension study was suspended to investigate a fatal thrombotic event. The suspension was lifted 3 months later, and the trial continued with reduced doses of replacement factors or bypassing agents for breakthrough bleeds.

The pause in the study was used to gather data about the effects of dosing cessation and resumption, which were reported by coauthor Craig Benson, MD, of Sanofi Genzyme in Cambridge, Mass. Dr. Benson presented findings at the annual congress of the European Association for Haemophilia and Allied Disorders on behalf of lead author John Pasi, MD, PhD, of the Haemophilia Centre at the Royal London Hospital and colleagues.

Prior to the suspension, 28 patients with hemophilia A or B, with or without inhibitors, were given 50-80 mg of fitusiran for up to 20 months with a median dose duration of 11 months. During dosing suspension, the investigators measured AT levels, thrombin generation, and annualized bleeding rates (ABR).

“We can see that the antithrombin knockdown effect of fitusiran is reversible with dosing hold,” Dr. Benson said, referring to an upward trend of median AT level.

Within 4 months of stopping fitusiran, median AT level was 60% of normal. This level continued to rise to about 90% by month 7, before returning to normal at month 11.

“This is an AT recovery we had previously seen by a few subjects that had discontinued [fitusiran] prior to the clinical hold,” Dr. Benson said, “but here, with a much larger sample size, we see a fairly consistent AT recovery.”

As expected, while AT levels rose, thrombin generation showed an inverse trend. “We see a similar temporal pattern,” Dr. Benson said. “The bulk of thrombin generation decrease is seen by the 4th month off fitusiran.”

When patients restarted fitusiran after the suspension was lifted, AT levels dropped to about 30% of normal by month 1 and about 20% of normal from month 2 onward. Again, in an inverse manner, thrombin generation increased.

Clinically, changes in AT and thrombin generation before, during, and after study suspension were reflected in median ABR, which rose from 1.43 events per year prior to cessation to 6.47 events per year during treatment hold before falling to 1.25 events per year after restarting fitusiran.

Overall, the results support the efficacy and reversibility of fitusiran. The agent is continuing to be studied in the phase 3 ATLAS trials.

The study was funded by Sanofi Genzyme and Alnylam. Dr. Benson is an employee of Sanofi Genzyme. Other investigators reported financial ties to Sanofi Genzyme, Alnylam, Baxalta, Octapharma, Pfizer, Shire, and others.

SOURCE: Pasi J et al. EAHAD 2019, Abstract OR16.

ANSWER

The radiograph shows a right knee prosthesis in place with no evidence of failure or displacement. Of note, there is a hyperdense, somewhat elongated lesion along the distal third of the femur. Radiographically, this is most likely consistent with an enchondroma. Enchondromas are typically benign bone lesions that originate from cartilage. They seldom cause pain and are usually found incidentally. No specific treatment is warranted.

The patient was referred to his orthopedist for follow-up.

ANSWER

The radiograph shows a right knee prosthesis in place with no evidence of failure or displacement. Of note, there is a hyperdense, somewhat elongated lesion along the distal third of the femur. Radiographically, this is most likely consistent with an enchondroma. Enchondromas are typically benign bone lesions that originate from cartilage. They seldom cause pain and are usually found incidentally. No specific treatment is warranted.

The patient was referred to his orthopedist for follow-up.

ANSWER

The radiograph shows a right knee prosthesis in place with no evidence of failure or displacement. Of note, there is a hyperdense, somewhat elongated lesion along the distal third of the femur. Radiographically, this is most likely consistent with an enchondroma. Enchondromas are typically benign bone lesions that originate from cartilage. They seldom cause pain and are usually found incidentally. No specific treatment is warranted.

The patient was referred to his orthopedist for follow-up.

To the Editor:

Specific characteristics of a lymphocytic infiltrate noted on frozen section histologic examination during Mohs micrographic surgery (MMS) tumor excision should raise suspicion of an underlying chronic lymphocytic leukemia (CLL). This infiltrate may be the presenting sign of the underlying leukemia and has variable presentation that may mimic aggressive features. The following 3 cases highlight this phenomenon.

A 74-year-old man (patient 1) with a medical history of multiple nonmelanoma skin cancers (NMSCs) presented for definitive treatment of a biopsy-proven infiltrative basal cell carcinoma involving the right infra-auricular region. Mohs section histologic evaluation revealed patches of lymphocytic infiltrates so dense they obscured the tumor margins. The lymphocytic infiltrates persisted even after 3 MMS stages, though they were moderately less dense compared to the initial MMS stage. Clinical interpretation determined no relationship between the lymphocytic infiltrates and residual tumor. Due to concerns that this lymphocytic infiltrate may indicate an underlying leukemic process, preoperative laboratory tests were ordered prior to closure of the surgical wound, which demonstrated an elevated white blood cell count of 65,000/µL (reference range, 4500–11,000/µL) with 93% lymphocytes. A follow-up complete blood cell count (CBC) and blood smear confirmed the diagnosis of CLL. The patient was referred to a hematologist/oncologist.

An 84-year old man (patient 2) with a medical history of numerous precancerous lesions and 1 squamous cell carcinoma (SCC) presented for a biopsy, which determined moderately differentiated SCC. Mohs micrographic surgery was performed. The initial stage of MMS histologic examination demonstrated basosquamous carcinoma in the specimen margins, including perineural growth, with an extensive lymphoid infiltrate surrounding the tumor (Figure 1). A second stage of MMS was performed, and although margins appeared to be clear of the basosquamous histology, complete assessment was difficult due to areas of dense inflammatory infiltrate (Figure 2), including perineural infiltration that remained and appeared to extend deeper into the tissues. Pathology was consulted and it was determined that the perineural infiltration was unlikely related to tumor spread but rather secondary to an unknown cause. Further investigation of the patient’s medical history revealed previously diagnosed CLL, which had been omitted by the patient, as he had forgotten this diagnosis and denied a history of cancer, lymphoma, and even leukemia. A query to the patient’s primary care physician found the most recent CBC demonstrated an elevated white blood cell count of 37,600/µL with 78% lymphocytes.

An 84-year-old man (patient 3) with a known history of CLL was referred for MMS excision of a 3.5×4.0-cm SCC on the right anterior temple extending onto the lateral upper and lower eyelids. Mohs frozen section histologic examination of excised tissue revealed patches of heavy lymphocytic infiltrates not found exclusively around the residual tumor but additionally around superficial and deep neurovascular bundles. The second stage of MMS appeared to be clear of tumor cells, but lymphocytic infiltrates remained. Because this patient had a clear history of CLL, the decision was made in conjunction with a dermatopathologist to conclude the surgery at this point. However, secondary to the aggressive, deeply invasive growth of this SCC, the patient was referred for adjunctive radiation therapy to the surgical site after wound reconstruction.

Chronic lymphocytic leukemia is the most common leukemia in the Western world¹ and is estimated to account for 27% of all new cases of leukemia. An individual’s lifetime risk is 0.5%. Chronic lymphocytic leukemia is predominantly a disease of the elderly, with an average age at diagnosis of 71 years. It is more common among males, North American and European populations, and those with a positive family history. Although epidemiologic factors including farming, prolonged pesticide exposure, and contact with Agent Orange have tentative links to CLL, the relationships are poorly established.²

Symptoms associated with acute leukemia only rarely manifest in patients with CLL.³ If present, symptoms are vague and include weakness, fatigue, weight loss, fever, night sweats, and a feeling of abdominal fullness.^2,3 On clinical examination, patients also may have lymphadenopathy, splenomegaly, or hepatomegaly. Increasing severity of symptoms at time of presentation directly correlates with the severity and staging at the time of diagnosis.⁴ Not only do patients with CLL have a greater incidence of NMSCs with more notable subclinical tumor extension than the average person, but these individuals also have a greatly increased risk for skin cancer recurrence posttreatment.^5,6

Although tissue pathology is not routinely part of the diagnosis of patients with CLL, findings can add to clinical suspicion. Smudge cells, which are cell debris, are characteristic morphologic features found in CLL. Most CLL cells are characteristically small mature lymphocytes with a dense nucleus.³ The presence of aggregates of these cells may obscure tumor margins during resection of NMSCs.⁷ This infiltrate is present in more than one-third of patients with CLL, as described in one retrospective cohort. This study simultaneously demonstrated the relationship between CLL and a 2-fold increase in postoperative defect size, which was attributed to either subclinical tumor spread or extra tissue removal to ensure clearance due to the leukemic infiltrates themselves.⁸ The presence of perineural tumor growth, which can occur with aggressive SCC and basal cell carcinoma, may be mimicked by perineural involvement of CLL cells rather than the reactive inflammation associated with continued tumor margins.⁷

When evaluating a patient with suspected CLL, laboratory tests should include a CBC with differential and examination of the peripheral smear. If abnormal, immunophenotyping of lymphocytes by flow cytometry will rule out other lymphoproliferative diseases and verify CLL as the diagnosis.³ Diagnosis of CLL requires the presence of monoclonal B lymphocytes (≥5×10⁹/L) in the peripheral blood as confirmed by flow cytometry.³ Clonality of circulating B lymphocytes must be confirmed, and immunophenotyping will establish a diagnosis with leukemic cells having positive expression of CD20 (Figure 3A) and CD23 (Figure 3B)(characteristic of B-cell lineage) with coexpression of CD43 and CD5 (Figure 3C)(characteristic of T-cell lineage).^7,9 This pattern of immunohistochemical markers can be differentiated from the normal immune response to cutaneous malignancies, which have the pattern of being CD3⁺, CD5⁺, and CD43⁺ with absence of B-cell markers (ie, CD20, CD23)(Table).⁷

The pathogenesis of this peritumoral infiltrate is unknown, though multiple theories exist. One theory is that the neoplastic lymphocytes are responding as a dysfunctional arm of the immune system to tumor-specific antigens. In patients with CLL, leukemic lymphocytes comprise a large portion of the circulating leukocyte population and this peritumoral infiltrate may simply be a reflection of the circulating leukocytic population. Another theory contends that neoplastic lymphocytes are simply nonspecific aggregations secondary to tumor neovascularization and increased vascular permeability.¹⁰

This neoplastic infiltrate seen incidentally during MMS excision of NMSCs not only provides a unique opportunity to diagnose and intervene in those with unknown CLL but also to be aware of complicating features that can spare the patient from unnecessary tissue removal, thereby maximizing the benefit of MMS. This infiltrate can obscure tumor margins; is unusually dense and patchy, with or without infiltrating perineural or perivascular components; and persists beyond what would seem to be an adequate margin to clear a tumor. These cases show these findings, which exemplify the peritumoral infiltrate of CLL and should prompt further workup.

To the Editor:

Specific characteristics of a lymphocytic infiltrate noted on frozen section histologic examination during Mohs micrographic surgery (MMS) tumor excision should raise suspicion of an underlying chronic lymphocytic leukemia (CLL). This infiltrate may be the presenting sign of the underlying leukemia and has variable presentation that may mimic aggressive features. The following 3 cases highlight this phenomenon.

A 74-year-old man (patient 1) with a medical history of multiple nonmelanoma skin cancers (NMSCs) presented for definitive treatment of a biopsy-proven infiltrative basal cell carcinoma involving the right infra-auricular region. Mohs section histologic evaluation revealed patches of lymphocytic infiltrates so dense they obscured the tumor margins. The lymphocytic infiltrates persisted even after 3 MMS stages, though they were moderately less dense compared to the initial MMS stage. Clinical interpretation determined no relationship between the lymphocytic infiltrates and residual tumor. Due to concerns that this lymphocytic infiltrate may indicate an underlying leukemic process, preoperative laboratory tests were ordered prior to closure of the surgical wound, which demonstrated an elevated white blood cell count of 65,000/µL (reference range, 4500–11,000/µL) with 93% lymphocytes. A follow-up complete blood cell count (CBC) and blood smear confirmed the diagnosis of CLL. The patient was referred to a hematologist/oncologist.

An 84-year old man (patient 2) with a medical history of numerous precancerous lesions and 1 squamous cell carcinoma (SCC) presented for a biopsy, which determined moderately differentiated SCC. Mohs micrographic surgery was performed. The initial stage of MMS histologic examination demonstrated basosquamous carcinoma in the specimen margins, including perineural growth, with an extensive lymphoid infiltrate surrounding the tumor (Figure 1). A second stage of MMS was performed, and although margins appeared to be clear of the basosquamous histology, complete assessment was difficult due to areas of dense inflammatory infiltrate (Figure 2), including perineural infiltration that remained and appeared to extend deeper into the tissues. Pathology was consulted and it was determined that the perineural infiltration was unlikely related to tumor spread but rather secondary to an unknown cause. Further investigation of the patient’s medical history revealed previously diagnosed CLL, which had been omitted by the patient, as he had forgotten this diagnosis and denied a history of cancer, lymphoma, and even leukemia. A query to the patient’s primary care physician found the most recent CBC demonstrated an elevated white blood cell count of 37,600/µL with 78% lymphocytes.

An 84-year-old man (patient 3) with a known history of CLL was referred for MMS excision of a 3.5×4.0-cm SCC on the right anterior temple extending onto the lateral upper and lower eyelids. Mohs frozen section histologic examination of excised tissue revealed patches of heavy lymphocytic infiltrates not found exclusively around the residual tumor but additionally around superficial and deep neurovascular bundles. The second stage of MMS appeared to be clear of tumor cells, but lymphocytic infiltrates remained. Because this patient had a clear history of CLL, the decision was made in conjunction with a dermatopathologist to conclude the surgery at this point. However, secondary to the aggressive, deeply invasive growth of this SCC, the patient was referred for adjunctive radiation therapy to the surgical site after wound reconstruction.

Chronic lymphocytic leukemia is the most common leukemia in the Western world¹ and is estimated to account for 27% of all new cases of leukemia. An individual’s lifetime risk is 0.5%. Chronic lymphocytic leukemia is predominantly a disease of the elderly, with an average age at diagnosis of 71 years. It is more common among males, North American and European populations, and those with a positive family history. Although epidemiologic factors including farming, prolonged pesticide exposure, and contact with Agent Orange have tentative links to CLL, the relationships are poorly established.²

Symptoms associated with acute leukemia only rarely manifest in patients with CLL.³ If present, symptoms are vague and include weakness, fatigue, weight loss, fever, night sweats, and a feeling of abdominal fullness.^2,3 On clinical examination, patients also may have lymphadenopathy, splenomegaly, or hepatomegaly. Increasing severity of symptoms at time of presentation directly correlates with the severity and staging at the time of diagnosis.⁴ Not only do patients with CLL have a greater incidence of NMSCs with more notable subclinical tumor extension than the average person, but these individuals also have a greatly increased risk for skin cancer recurrence posttreatment.^5,6

Although tissue pathology is not routinely part of the diagnosis of patients with CLL, findings can add to clinical suspicion. Smudge cells, which are cell debris, are characteristic morphologic features found in CLL. Most CLL cells are characteristically small mature lymphocytes with a dense nucleus.³ The presence of aggregates of these cells may obscure tumor margins during resection of NMSCs.⁷ This infiltrate is present in more than one-third of patients with CLL, as described in one retrospective cohort. This study simultaneously demonstrated the relationship between CLL and a 2-fold increase in postoperative defect size, which was attributed to either subclinical tumor spread or extra tissue removal to ensure clearance due to the leukemic infiltrates themselves.⁸ The presence of perineural tumor growth, which can occur with aggressive SCC and basal cell carcinoma, may be mimicked by perineural involvement of CLL cells rather than the reactive inflammation associated with continued tumor margins.⁷

When evaluating a patient with suspected CLL, laboratory tests should include a CBC with differential and examination of the peripheral smear. If abnormal, immunophenotyping of lymphocytes by flow cytometry will rule out other lymphoproliferative diseases and verify CLL as the diagnosis.³ Diagnosis of CLL requires the presence of monoclonal B lymphocytes (≥5×10⁹/L) in the peripheral blood as confirmed by flow cytometry.³ Clonality of circulating B lymphocytes must be confirmed, and immunophenotyping will establish a diagnosis with leukemic cells having positive expression of CD20 (Figure 3A) and CD23 (Figure 3B)(characteristic of B-cell lineage) with coexpression of CD43 and CD5 (Figure 3C)(characteristic of T-cell lineage).^7,9 This pattern of immunohistochemical markers can be differentiated from the normal immune response to cutaneous malignancies, which have the pattern of being CD3⁺, CD5⁺, and CD43⁺ with absence of B-cell markers (ie, CD20, CD23)(Table).⁷

The pathogenesis of this peritumoral infiltrate is unknown, though multiple theories exist. One theory is that the neoplastic lymphocytes are responding as a dysfunctional arm of the immune system to tumor-specific antigens. In patients with CLL, leukemic lymphocytes comprise a large portion of the circulating leukocyte population and this peritumoral infiltrate may simply be a reflection of the circulating leukocytic population. Another theory contends that neoplastic lymphocytes are simply nonspecific aggregations secondary to tumor neovascularization and increased vascular permeability.¹⁰

This neoplastic infiltrate seen incidentally during MMS excision of NMSCs not only provides a unique opportunity to diagnose and intervene in those with unknown CLL but also to be aware of complicating features that can spare the patient from unnecessary tissue removal, thereby maximizing the benefit of MMS. This infiltrate can obscure tumor margins; is unusually dense and patchy, with or without infiltrating perineural or perivascular components; and persists beyond what would seem to be an adequate margin to clear a tumor. These cases show these findings, which exemplify the peritumoral infiltrate of CLL and should prompt further workup.

To the Editor:

Specific characteristics of a lymphocytic infiltrate noted on frozen section histologic examination during Mohs micrographic surgery (MMS) tumor excision should raise suspicion of an underlying chronic lymphocytic leukemia (CLL). This infiltrate may be the presenting sign of the underlying leukemia and has variable presentation that may mimic aggressive features. The following 3 cases highlight this phenomenon.

A 74-year-old man (patient 1) with a medical history of multiple nonmelanoma skin cancers (NMSCs) presented for definitive treatment of a biopsy-proven infiltrative basal cell carcinoma involving the right infra-auricular region. Mohs section histologic evaluation revealed patches of lymphocytic infiltrates so dense they obscured the tumor margins. The lymphocytic infiltrates persisted even after 3 MMS stages, though they were moderately less dense compared to the initial MMS stage. Clinical interpretation determined no relationship between the lymphocytic infiltrates and residual tumor. Due to concerns that this lymphocytic infiltrate may indicate an underlying leukemic process, preoperative laboratory tests were ordered prior to closure of the surgical wound, which demonstrated an elevated white blood cell count of 65,000/µL (reference range, 4500–11,000/µL) with 93% lymphocytes. A follow-up complete blood cell count (CBC) and blood smear confirmed the diagnosis of CLL. The patient was referred to a hematologist/oncologist.

An 84-year old man (patient 2) with a medical history of numerous precancerous lesions and 1 squamous cell carcinoma (SCC) presented for a biopsy, which determined moderately differentiated SCC. Mohs micrographic surgery was performed. The initial stage of MMS histologic examination demonstrated basosquamous carcinoma in the specimen margins, including perineural growth, with an extensive lymphoid infiltrate surrounding the tumor (Figure 1). A second stage of MMS was performed, and although margins appeared to be clear of the basosquamous histology, complete assessment was difficult due to areas of dense inflammatory infiltrate (Figure 2), including perineural infiltration that remained and appeared to extend deeper into the tissues. Pathology was consulted and it was determined that the perineural infiltration was unlikely related to tumor spread but rather secondary to an unknown cause. Further investigation of the patient’s medical history revealed previously diagnosed CLL, which had been omitted by the patient, as he had forgotten this diagnosis and denied a history of cancer, lymphoma, and even leukemia. A query to the patient’s primary care physician found the most recent CBC demonstrated an elevated white blood cell count of 37,600/µL with 78% lymphocytes.

An 84-year-old man (patient 3) with a known history of CLL was referred for MMS excision of a 3.5×4.0-cm SCC on the right anterior temple extending onto the lateral upper and lower eyelids. Mohs frozen section histologic examination of excised tissue revealed patches of heavy lymphocytic infiltrates not found exclusively around the residual tumor but additionally around superficial and deep neurovascular bundles. The second stage of MMS appeared to be clear of tumor cells, but lymphocytic infiltrates remained. Because this patient had a clear history of CLL, the decision was made in conjunction with a dermatopathologist to conclude the surgery at this point. However, secondary to the aggressive, deeply invasive growth of this SCC, the patient was referred for adjunctive radiation therapy to the surgical site after wound reconstruction.

Chronic lymphocytic leukemia is the most common leukemia in the Western world¹ and is estimated to account for 27% of all new cases of leukemia. An individual’s lifetime risk is 0.5%. Chronic lymphocytic leukemia is predominantly a disease of the elderly, with an average age at diagnosis of 71 years. It is more common among males, North American and European populations, and those with a positive family history. Although epidemiologic factors including farming, prolonged pesticide exposure, and contact with Agent Orange have tentative links to CLL, the relationships are poorly established.²

Symptoms associated with acute leukemia only rarely manifest in patients with CLL.³ If present, symptoms are vague and include weakness, fatigue, weight loss, fever, night sweats, and a feeling of abdominal fullness.^2,3 On clinical examination, patients also may have lymphadenopathy, splenomegaly, or hepatomegaly. Increasing severity of symptoms at time of presentation directly correlates with the severity and staging at the time of diagnosis.⁴ Not only do patients with CLL have a greater incidence of NMSCs with more notable subclinical tumor extension than the average person, but these individuals also have a greatly increased risk for skin cancer recurrence posttreatment.^5,6

Although tissue pathology is not routinely part of the diagnosis of patients with CLL, findings can add to clinical suspicion. Smudge cells, which are cell debris, are characteristic morphologic features found in CLL. Most CLL cells are characteristically small mature lymphocytes with a dense nucleus.³ The presence of aggregates of these cells may obscure tumor margins during resection of NMSCs.⁷ This infiltrate is present in more than one-third of patients with CLL, as described in one retrospective cohort. This study simultaneously demonstrated the relationship between CLL and a 2-fold increase in postoperative defect size, which was attributed to either subclinical tumor spread or extra tissue removal to ensure clearance due to the leukemic infiltrates themselves.⁸ The presence of perineural tumor growth, which can occur with aggressive SCC and basal cell carcinoma, may be mimicked by perineural involvement of CLL cells rather than the reactive inflammation associated with continued tumor margins.⁷

When evaluating a patient with suspected CLL, laboratory tests should include a CBC with differential and examination of the peripheral smear. If abnormal, immunophenotyping of lymphocytes by flow cytometry will rule out other lymphoproliferative diseases and verify CLL as the diagnosis.³ Diagnosis of CLL requires the presence of monoclonal B lymphocytes (≥5×10⁹/L) in the peripheral blood as confirmed by flow cytometry.³ Clonality of circulating B lymphocytes must be confirmed, and immunophenotyping will establish a diagnosis with leukemic cells having positive expression of CD20 (Figure 3A) and CD23 (Figure 3B)(characteristic of B-cell lineage) with coexpression of CD43 and CD5 (Figure 3C)(characteristic of T-cell lineage).^7,9 This pattern of immunohistochemical markers can be differentiated from the normal immune response to cutaneous malignancies, which have the pattern of being CD3⁺, CD5⁺, and CD43⁺ with absence of B-cell markers (ie, CD20, CD23)(Table).⁷

The pathogenesis of this peritumoral infiltrate is unknown, though multiple theories exist. One theory is that the neoplastic lymphocytes are responding as a dysfunctional arm of the immune system to tumor-specific antigens. In patients with CLL, leukemic lymphocytes comprise a large portion of the circulating leukocyte population and this peritumoral infiltrate may simply be a reflection of the circulating leukocytic population. Another theory contends that neoplastic lymphocytes are simply nonspecific aggregations secondary to tumor neovascularization and increased vascular permeability.¹⁰

This neoplastic infiltrate seen incidentally during MMS excision of NMSCs not only provides a unique opportunity to diagnose and intervene in those with unknown CLL but also to be aware of complicating features that can spare the patient from unnecessary tissue removal, thereby maximizing the benefit of MMS. This infiltrate can obscure tumor margins; is unusually dense and patchy, with or without infiltrating perineural or perivascular components; and persists beyond what would seem to be an adequate margin to clear a tumor. These cases show these findings, which exemplify the peritumoral infiltrate of CLL and should prompt further workup.

Nivolumab may provide a benefit for a small group of patients with diffuse large B-cell lymphoma (DLBCL) who have failed a transplant or are ineligible for one, according to researchers.

Nivolumab produced a response in 10 of 121 DLBCL patients studied. Three patients achieved a complete response (CR) lasting 11 months or more.

Why this small group responded to nivolumab isn’t clear, according to Stephen M. Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minn., and his colleagues.

Some responders did have 9p24.1 alterations, but others did not. None of the responders had tumor cells positive for programmed death–ligand 1 (PD-L1), and only one responder had detectable PD-L2 expression in malignant cells.

Dr. Ansell and his colleagues described these findings in the Journal of Clinical Oncology.

The researchers evaluated nivolumab in a phase 2 trial (NCT02038933) of patients with relapsed/refractory DLBCL. Of the 121 patients, 87 had failed autologous hematopoietic stem cell transplant (HSCT) and 34 were ineligible for autologous HSCT. The patients received nivolumab at 3 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or study withdrawal.

HSCT failures

The patients who had failed HSCT had a median age of 62 years (range, 24-75 years). They had received a median of three prior systemic therapies (range, 1-11), and 28% were refractory to their most recent therapy.

About 40% of patients had germinal center B-cell–like (GCB) DLBCL, 32% had non-GCB disease, and data on disease subtype were missing for the rest of the group.

The patients received a median of four nivolumab doses (range, 1-44) and were followed for a median of 9 months (range, 0.1-25 months).

Nine patients (10%) achieved a response, and the median duration of response was 11 months. Responses occurred in patients with GCB and non-GCB DLBCL.

Three patients achieved a CR. Two of them were still on treatment and in CR at the data cutoff. Their responses had lasted 11 months and 14 months, respectively. The third complete responder did not progress on nivolumab but developed myelodysplastic syndrome, which was unrelated to the drug, and died.

Among all patients who had failed HSCT, the median progression-free survival was 1.9 months, and the median overall survival was 12.2 months.

Seven patients in this group were still receiving nivolumab at the data cutoff. Two of them were in CR, two had a partial response, and three had stable disease.

HSCT-ineligible group

The patients who were ineligible for HSCT had a median age of 68 years (range, 28-86 years). They had received a median of three prior systemic therapies (range, 1-7), and 59% were refractory to their most recent therapy.

About 56% of these patients had GCB DLBCL, 18% had non-GCB disease, and data on subtype were missing for the rest of the group.

The patients received a median of three nivolumab doses (range, 1-22) and were followed for a median of 6 months (range, 0.2-24 months). One patient (3%) achieved a partial response, which lasted 8.3 months.

The median progression-free survival in this group was 1.4 months, and the median overall survival was 5.8 months.

None of the patients in this group were still taking nivolumab at the data cutoff.

Biomarkers of response

Dr. Ansell and his colleagues were able to look for 9p24.1 alterations in archival tumor biopsy specimens from 74 patients. The team reported that 9p24.1 alterations were “infrequent,” but they were found in some responders.

Among the three complete responders, one patient had high-level 9p24.1 amplification, one had normal 9p24.1 copy number, and one did not have a biopsy available.

Among the seven patients who achieved a partial response, five had biopsy specimens. Three patients had low-level polysomy, one had copy gain, and one patient had normal 9p24.1.

None of the responders had PD-L1 expression in their tumor cells, but one complete responder had PD-L2–positive malignant cells.

Dr. Ansell and his colleagues wrote that the “biologic basis for response in the other two [complete responders] is unclear,” and the researchers were unable to assess associations between response and c-myc expression or double-hit lymphoma.

Safety

Of all 121 patients, 62% had a treatment-related adverse event (AE) and 24% had a grade 3/4–related AE.

The most common related AEs of any grade were nausea (17%), fatigue (17%), diarrhea (10%), neutropenia (7%), thrombocytopenia (6%), decreased appetite (6%), lipase increase (5%), rash (5%), and pyrexia (5%).

Four patients (3%) stopped taking nivolumab because of treatment-related AEs, including neutropenia, thrombocytopenia, diarrhea, pancreatitis, lipase increase, and psoriasiform dermatitis. There were no fatal treatment-related AEs.

This research was supported by Bristol-Myers Squibb and other groups. The study authors reported relationships with Bristol-Myers Squibb and other companies.

[email protected]

SOURCE: Ansell SM et al. J Clin Oncol. 2019 Jan 8. doi: 10.1200/JCO.18.00766.

Nivolumab may provide a benefit for a small group of patients with diffuse large B-cell lymphoma (DLBCL) who have failed a transplant or are ineligible for one, according to researchers.

Nivolumab produced a response in 10 of 121 DLBCL patients studied. Three patients achieved a complete response (CR) lasting 11 months or more.

Why this small group responded to nivolumab isn’t clear, according to Stephen M. Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minn., and his colleagues.

Some responders did have 9p24.1 alterations, but others did not. None of the responders had tumor cells positive for programmed death–ligand 1 (PD-L1), and only one responder had detectable PD-L2 expression in malignant cells.

Dr. Ansell and his colleagues described these findings in the Journal of Clinical Oncology.

The researchers evaluated nivolumab in a phase 2 trial (NCT02038933) of patients with relapsed/refractory DLBCL. Of the 121 patients, 87 had failed autologous hematopoietic stem cell transplant (HSCT) and 34 were ineligible for autologous HSCT. The patients received nivolumab at 3 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or study withdrawal.

HSCT failures

The patients who had failed HSCT had a median age of 62 years (range, 24-75 years). They had received a median of three prior systemic therapies (range, 1-11), and 28% were refractory to their most recent therapy.

About 40% of patients had germinal center B-cell–like (GCB) DLBCL, 32% had non-GCB disease, and data on disease subtype were missing for the rest of the group.

The patients received a median of four nivolumab doses (range, 1-44) and were followed for a median of 9 months (range, 0.1-25 months).

Nine patients (10%) achieved a response, and the median duration of response was 11 months. Responses occurred in patients with GCB and non-GCB DLBCL.

Three patients achieved a CR. Two of them were still on treatment and in CR at the data cutoff. Their responses had lasted 11 months and 14 months, respectively. The third complete responder did not progress on nivolumab but developed myelodysplastic syndrome, which was unrelated to the drug, and died.

Among all patients who had failed HSCT, the median progression-free survival was 1.9 months, and the median overall survival was 12.2 months.

Seven patients in this group were still receiving nivolumab at the data cutoff. Two of them were in CR, two had a partial response, and three had stable disease.

HSCT-ineligible group

The patients who were ineligible for HSCT had a median age of 68 years (range, 28-86 years). They had received a median of three prior systemic therapies (range, 1-7), and 59% were refractory to their most recent therapy.

About 56% of these patients had GCB DLBCL, 18% had non-GCB disease, and data on subtype were missing for the rest of the group.

The patients received a median of three nivolumab doses (range, 1-22) and were followed for a median of 6 months (range, 0.2-24 months). One patient (3%) achieved a partial response, which lasted 8.3 months.

The median progression-free survival in this group was 1.4 months, and the median overall survival was 5.8 months.

None of the patients in this group were still taking nivolumab at the data cutoff.

Biomarkers of response

Dr. Ansell and his colleagues were able to look for 9p24.1 alterations in archival tumor biopsy specimens from 74 patients. The team reported that 9p24.1 alterations were “infrequent,” but they were found in some responders.

Among the three complete responders, one patient had high-level 9p24.1 amplification, one had normal 9p24.1 copy number, and one did not have a biopsy available.

Among the seven patients who achieved a partial response, five had biopsy specimens. Three patients had low-level polysomy, one had copy gain, and one patient had normal 9p24.1.

None of the responders had PD-L1 expression in their tumor cells, but one complete responder had PD-L2–positive malignant cells.

Dr. Ansell and his colleagues wrote that the “biologic basis for response in the other two [complete responders] is unclear,” and the researchers were unable to assess associations between response and c-myc expression or double-hit lymphoma.

Safety

Of all 121 patients, 62% had a treatment-related adverse event (AE) and 24% had a grade 3/4–related AE.

The most common related AEs of any grade were nausea (17%), fatigue (17%), diarrhea (10%), neutropenia (7%), thrombocytopenia (6%), decreased appetite (6%), lipase increase (5%), rash (5%), and pyrexia (5%).

Four patients (3%) stopped taking nivolumab because of treatment-related AEs, including neutropenia, thrombocytopenia, diarrhea, pancreatitis, lipase increase, and psoriasiform dermatitis. There were no fatal treatment-related AEs.

This research was supported by Bristol-Myers Squibb and other groups. The study authors reported relationships with Bristol-Myers Squibb and other companies.

[email protected]

SOURCE: Ansell SM et al. J Clin Oncol. 2019 Jan 8. doi: 10.1200/JCO.18.00766.

Nivolumab may provide a benefit for a small group of patients with diffuse large B-cell lymphoma (DLBCL) who have failed a transplant or are ineligible for one, according to researchers.

Nivolumab produced a response in 10 of 121 DLBCL patients studied. Three patients achieved a complete response (CR) lasting 11 months or more.

Why this small group responded to nivolumab isn’t clear, according to Stephen M. Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minn., and his colleagues.

Some responders did have 9p24.1 alterations, but others did not. None of the responders had tumor cells positive for programmed death–ligand 1 (PD-L1), and only one responder had detectable PD-L2 expression in malignant cells.

Dr. Ansell and his colleagues described these findings in the Journal of Clinical Oncology.

The researchers evaluated nivolumab in a phase 2 trial (NCT02038933) of patients with relapsed/refractory DLBCL. Of the 121 patients, 87 had failed autologous hematopoietic stem cell transplant (HSCT) and 34 were ineligible for autologous HSCT. The patients received nivolumab at 3 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or study withdrawal.

HSCT failures

The patients who had failed HSCT had a median age of 62 years (range, 24-75 years). They had received a median of three prior systemic therapies (range, 1-11), and 28% were refractory to their most recent therapy.

About 40% of patients had germinal center B-cell–like (GCB) DLBCL, 32% had non-GCB disease, and data on disease subtype were missing for the rest of the group.

The patients received a median of four nivolumab doses (range, 1-44) and were followed for a median of 9 months (range, 0.1-25 months).

Nine patients (10%) achieved a response, and the median duration of response was 11 months. Responses occurred in patients with GCB and non-GCB DLBCL.

Three patients achieved a CR. Two of them were still on treatment and in CR at the data cutoff. Their responses had lasted 11 months and 14 months, respectively. The third complete responder did not progress on nivolumab but developed myelodysplastic syndrome, which was unrelated to the drug, and died.

Among all patients who had failed HSCT, the median progression-free survival was 1.9 months, and the median overall survival was 12.2 months.

Seven patients in this group were still receiving nivolumab at the data cutoff. Two of them were in CR, two had a partial response, and three had stable disease.

HSCT-ineligible group

The patients who were ineligible for HSCT had a median age of 68 years (range, 28-86 years). They had received a median of three prior systemic therapies (range, 1-7), and 59% were refractory to their most recent therapy.

About 56% of these patients had GCB DLBCL, 18% had non-GCB disease, and data on subtype were missing for the rest of the group.

The patients received a median of three nivolumab doses (range, 1-22) and were followed for a median of 6 months (range, 0.2-24 months). One patient (3%) achieved a partial response, which lasted 8.3 months.

The median progression-free survival in this group was 1.4 months, and the median overall survival was 5.8 months.

None of the patients in this group were still taking nivolumab at the data cutoff.

Biomarkers of response

Dr. Ansell and his colleagues were able to look for 9p24.1 alterations in archival tumor biopsy specimens from 74 patients. The team reported that 9p24.1 alterations were “infrequent,” but they were found in some responders.

Among the three complete responders, one patient had high-level 9p24.1 amplification, one had normal 9p24.1 copy number, and one did not have a biopsy available.

Among the seven patients who achieved a partial response, five had biopsy specimens. Three patients had low-level polysomy, one had copy gain, and one patient had normal 9p24.1.

None of the responders had PD-L1 expression in their tumor cells, but one complete responder had PD-L2–positive malignant cells.

Dr. Ansell and his colleagues wrote that the “biologic basis for response in the other two [complete responders] is unclear,” and the researchers were unable to assess associations between response and c-myc expression or double-hit lymphoma.

Safety

Of all 121 patients, 62% had a treatment-related adverse event (AE) and 24% had a grade 3/4–related AE.

The most common related AEs of any grade were nausea (17%), fatigue (17%), diarrhea (10%), neutropenia (7%), thrombocytopenia (6%), decreased appetite (6%), lipase increase (5%), rash (5%), and pyrexia (5%).

Four patients (3%) stopped taking nivolumab because of treatment-related AEs, including neutropenia, thrombocytopenia, diarrhea, pancreatitis, lipase increase, and psoriasiform dermatitis. There were no fatal treatment-related AEs.

This research was supported by Bristol-Myers Squibb and other groups. The study authors reported relationships with Bristol-Myers Squibb and other companies.

[email protected]

SOURCE: Ansell SM et al. J Clin Oncol. 2019 Jan 8. doi: 10.1200/JCO.18.00766.