AGA recognizes members whose accomplishments demonstrate personal commitment to the GI field with the distinction of AGA fellowship. Apply today to the program to gain recognition as a distinguished AGA Fellow. AGA fellowships honor superior professional achievement in clinical, private, or academic practice, and in basic or clinical research.

AGA Fellows will be acknowledged in several ways, including a certificate commemorating their accomplishment and the privilege of using the prestigious designation “AGAF” in professional activities. AGA Fellows are also honored at Digestive Disease Week^® (DDW) and on the AGA website. View the full list of benefits and criteria today.

Learn more and complete the online application by visiting http://www.gastro.org/about/aga-fellows-program. The deadline for submissions is Monday, Aug. 22, 2016.

AGA recognizes members whose accomplishments demonstrate personal commitment to the GI field with the distinction of AGA fellowship. Apply today to the program to gain recognition as a distinguished AGA Fellow. AGA fellowships honor superior professional achievement in clinical, private, or academic practice, and in basic or clinical research.

AGA Fellows will be acknowledged in several ways, including a certificate commemorating their accomplishment and the privilege of using the prestigious designation “AGAF” in professional activities. AGA Fellows are also honored at Digestive Disease Week^® (DDW) and on the AGA website. View the full list of benefits and criteria today.

Learn more and complete the online application by visiting http://www.gastro.org/about/aga-fellows-program. The deadline for submissions is Monday, Aug. 22, 2016.

AGA recognizes members whose accomplishments demonstrate personal commitment to the GI field with the distinction of AGA fellowship. Apply today to the program to gain recognition as a distinguished AGA Fellow. AGA fellowships honor superior professional achievement in clinical, private, or academic practice, and in basic or clinical research.

AGA Fellows will be acknowledged in several ways, including a certificate commemorating their accomplishment and the privilege of using the prestigious designation “AGAF” in professional activities. AGA Fellows are also honored at Digestive Disease Week^® (DDW) and on the AGA website. View the full list of benefits and criteria today.

Learn more and complete the online application by visiting http://www.gastro.org/about/aga-fellows-program. The deadline for submissions is Monday, Aug. 22, 2016.

The AGA Community forum has spurred engagement and collaborations on many different professional levels since its launch in early May. Recently trending topics included viral hepatitis, fecal immunochemical testing, reimbursement, practice guidelines, women in GI, and fecal transplants.

It’s easy to incorporate your new networking tool in your day-to-day practice using the AGA Community mobile app. The app gives you around-the-clock handheld access to AGA members and the discussion topics and resources that matter to you.

Learn more by downloading the app, available in AGA App Central or search your mobile app store for AGA Community. You can also join the conversations through your web browser, http://community.gastro.org.

The AGA Community forum has spurred engagement and collaborations on many different professional levels since its launch in early May. Recently trending topics included viral hepatitis, fecal immunochemical testing, reimbursement, practice guidelines, women in GI, and fecal transplants.

It’s easy to incorporate your new networking tool in your day-to-day practice using the AGA Community mobile app. The app gives you around-the-clock handheld access to AGA members and the discussion topics and resources that matter to you.

Learn more by downloading the app, available in AGA App Central or search your mobile app store for AGA Community. You can also join the conversations through your web browser, http://community.gastro.org.

The AGA Community forum has spurred engagement and collaborations on many different professional levels since its launch in early May. Recently trending topics included viral hepatitis, fecal immunochemical testing, reimbursement, practice guidelines, women in GI, and fecal transplants.

It’s easy to incorporate your new networking tool in your day-to-day practice using the AGA Community mobile app. The app gives you around-the-clock handheld access to AGA members and the discussion topics and resources that matter to you.

Learn more by downloading the app, available in AGA App Central or search your mobile app store for AGA Community. You can also join the conversations through your web browser, http://community.gastro.org.

Diagnosis: Agminated blue nevus

Agminated blue nevi are aggregated clusters of nevi that appear blue due to their deep dermal location and the subsequent scattering of short wavelengths of light (Tyndall effect). The clusters are typically contained within a 10 cm area. The intervening background skin is usually without hyperpigmentation or skin discoloration, although speckled pigmentation can occur. Generally, all forms of agminated nevi likely result from a loss of heterozygosity (LOH) mutation in the somatic line of an embryo, inducing a localized predilection for the development of nevi.

The differential diagnosis for agminated blue nevi includes segmental melanocytic nevi, melanoma, and other agminated melanocytic nevi: benign melanocytic nevi, atypical or dysplastic nevi, and speckled lentiginous nevi (nevus spilus).  The distribution of the nevi can help narrow the differential, as segmental melanocytic nevi are less clustered and spread over a larger area than agminated blue nevi. Congenital nevi are present at birth or within a few months and often have unique features, including perifollicular pigmentary changes, hypertrichosis, and focal hypopigmentation. Acquired nevi (blue nevi, benign melanocytic nevi, and atypical or dysplastic nevi) usually descend over time from the dermal-epidermal junction to the dermis and typically become a lighter color. Lastly, the presence or absence of background pigmentation can help distinguish between agminated blue nevi and nevus spilus. Nevus spilus is a subtype of congenital melanocytic nevi with a similar aggregated appearance but has a characteristic background hyperpigmentation between the discrete nevi.

Agminated blue nevi and nevus spilus can be differentiated in the clinic by using a Wood’s lamp or performing a biopsy, which is not indicated unless atypia is present. If a non-speckled background hyperpigmentation is present on Wood’s lamp illumination, the diagnosis of nevus spilus may be more appropriate, as agminated blue nevi typically show no background pigmentation. A biopsy of the skin would allow for distinguishing between nevus spilus and agminated nevi based on the pigment within the surrounding skin. The presence of melanocytic hyperplasia within the skin surrounding the discrete nevi would support the diagnosis of nevus spilus.

The main concern with any melanocytic proliferation is the potential for transformation into a melanoma. In general, agminated nevi carry an increased melanoma risk. Specifically, congenital melanocytic nevi result in a <1-5% risk of melanoma depending on the lesion size. The risk of melanoma associated with agminated blue nevi is currently unknown, but it should be noted that individual blue nevi rarely become malignant. Since more than 50% of cutaneous melanomas develop without a preceding nevus, removal of nevi to reduce melanoma risk is not typically indicated, except in the case of a large congenital melanocytic nevi (>20cm). However, long-term surveillance is crucial for agminated blue nevi, especially if the individual has dysplastic nevus syndrome. If the involved nevi develop any features of atypia, a biopsy should be performed to assess for the development of a melanoma.

This case and photo were submitted by Dr. Damon McClain of Three Rivers Dermatology in Coraopolis, Pa., and Mark Ash, a medical student at East Carolina University, Greenville, N.C. 

Dr. Bilu Martin is in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit your case for possible publication, send an email to [email protected].

References:

1. Ashfaq A. Marghoob, Robin Blum, Robert Nossa, Klaus J. Busam, Dana Sachs, Allan Halpern. Agminated Atypical (Dysplastic) Nevi Case Report and Review of the Literature. Arch Dermatol. 2001;137(7):917-920.
2. Belinda Tan, Noah Craft, Lindy P. Fox, Lowell A. Goldsmith, Michael D. Tharp. Visual Dx. Blue Nevus. Accessed 2/11/16. Camila Roos Mariano da Rocha, Thaís Corsetti Grazziotin, Maria Carolina Widholzer Rey, Laura Luzzatto, Renan Rangel Bonamigo. Congenital agminated melanocytic nevus - Case report. An Bras Dermatol. 2013;88(6 Suppl 1):170-2.
3. Chris G. Adigun, Jeffrey D. Bernhard, Sarah Stein, Karen Wiss, Sheila Galbraith, Craig N. Burkhart, Dean Morrell, Lynn Garfunkel, Nancy Esterly. Visual Dx. Agminated Nevus. Accessed 2/11/16.
4. Julie V Schaffer and Jean L Bolognia. Acquired melanocytic nevi (moles). In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on February 11, 2016.)
5. Julie V Schaffer and Jean L Bolognia. Congenital melanocytic nevi. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on February 11, 2016.)
6. Maria A. Pizzichetta, H. Peter Soyer, Cesare Massone, Lorenzo Cerroni. Clinical and Dermoscopic Features of Agminated Blue Nevus. Arch Dermatol. 2007;143(9):1209-1226.

Diagnosis: Agminated blue nevus

Agminated blue nevi are aggregated clusters of nevi that appear blue due to their deep dermal location and the subsequent scattering of short wavelengths of light (Tyndall effect). The clusters are typically contained within a 10 cm area. The intervening background skin is usually without hyperpigmentation or skin discoloration, although speckled pigmentation can occur. Generally, all forms of agminated nevi likely result from a loss of heterozygosity (LOH) mutation in the somatic line of an embryo, inducing a localized predilection for the development of nevi.

The differential diagnosis for agminated blue nevi includes segmental melanocytic nevi, melanoma, and other agminated melanocytic nevi: benign melanocytic nevi, atypical or dysplastic nevi, and speckled lentiginous nevi (nevus spilus).  The distribution of the nevi can help narrow the differential, as segmental melanocytic nevi are less clustered and spread over a larger area than agminated blue nevi. Congenital nevi are present at birth or within a few months and often have unique features, including perifollicular pigmentary changes, hypertrichosis, and focal hypopigmentation. Acquired nevi (blue nevi, benign melanocytic nevi, and atypical or dysplastic nevi) usually descend over time from the dermal-epidermal junction to the dermis and typically become a lighter color. Lastly, the presence or absence of background pigmentation can help distinguish between agminated blue nevi and nevus spilus. Nevus spilus is a subtype of congenital melanocytic nevi with a similar aggregated appearance but has a characteristic background hyperpigmentation between the discrete nevi.

Agminated blue nevi and nevus spilus can be differentiated in the clinic by using a Wood’s lamp or performing a biopsy, which is not indicated unless atypia is present. If a non-speckled background hyperpigmentation is present on Wood’s lamp illumination, the diagnosis of nevus spilus may be more appropriate, as agminated blue nevi typically show no background pigmentation. A biopsy of the skin would allow for distinguishing between nevus spilus and agminated nevi based on the pigment within the surrounding skin. The presence of melanocytic hyperplasia within the skin surrounding the discrete nevi would support the diagnosis of nevus spilus.

The main concern with any melanocytic proliferation is the potential for transformation into a melanoma. In general, agminated nevi carry an increased melanoma risk. Specifically, congenital melanocytic nevi result in a <1-5% risk of melanoma depending on the lesion size. The risk of melanoma associated with agminated blue nevi is currently unknown, but it should be noted that individual blue nevi rarely become malignant. Since more than 50% of cutaneous melanomas develop without a preceding nevus, removal of nevi to reduce melanoma risk is not typically indicated, except in the case of a large congenital melanocytic nevi (>20cm). However, long-term surveillance is crucial for agminated blue nevi, especially if the individual has dysplastic nevus syndrome. If the involved nevi develop any features of atypia, a biopsy should be performed to assess for the development of a melanoma.

This case and photo were submitted by Dr. Damon McClain of Three Rivers Dermatology in Coraopolis, Pa., and Mark Ash, a medical student at East Carolina University, Greenville, N.C. 

Dr. Bilu Martin is in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit your case for possible publication, send an email to [email protected].

References:

1. Ashfaq A. Marghoob, Robin Blum, Robert Nossa, Klaus J. Busam, Dana Sachs, Allan Halpern. Agminated Atypical (Dysplastic) Nevi Case Report and Review of the Literature. Arch Dermatol. 2001;137(7):917-920.
2. Belinda Tan, Noah Craft, Lindy P. Fox, Lowell A. Goldsmith, Michael D. Tharp. Visual Dx. Blue Nevus. Accessed 2/11/16. Camila Roos Mariano da Rocha, Thaís Corsetti Grazziotin, Maria Carolina Widholzer Rey, Laura Luzzatto, Renan Rangel Bonamigo. Congenital agminated melanocytic nevus - Case report. An Bras Dermatol. 2013;88(6 Suppl 1):170-2.
3. Chris G. Adigun, Jeffrey D. Bernhard, Sarah Stein, Karen Wiss, Sheila Galbraith, Craig N. Burkhart, Dean Morrell, Lynn Garfunkel, Nancy Esterly. Visual Dx. Agminated Nevus. Accessed 2/11/16.
4. Julie V Schaffer and Jean L Bolognia. Acquired melanocytic nevi (moles). In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on February 11, 2016.)
5. Julie V Schaffer and Jean L Bolognia. Congenital melanocytic nevi. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on February 11, 2016.)
6. Maria A. Pizzichetta, H. Peter Soyer, Cesare Massone, Lorenzo Cerroni. Clinical and Dermoscopic Features of Agminated Blue Nevus. Arch Dermatol. 2007;143(9):1209-1226.

Diagnosis: Agminated blue nevus

Agminated blue nevi are aggregated clusters of nevi that appear blue due to their deep dermal location and the subsequent scattering of short wavelengths of light (Tyndall effect). The clusters are typically contained within a 10 cm area. The intervening background skin is usually without hyperpigmentation or skin discoloration, although speckled pigmentation can occur. Generally, all forms of agminated nevi likely result from a loss of heterozygosity (LOH) mutation in the somatic line of an embryo, inducing a localized predilection for the development of nevi.

The differential diagnosis for agminated blue nevi includes segmental melanocytic nevi, melanoma, and other agminated melanocytic nevi: benign melanocytic nevi, atypical or dysplastic nevi, and speckled lentiginous nevi (nevus spilus).  The distribution of the nevi can help narrow the differential, as segmental melanocytic nevi are less clustered and spread over a larger area than agminated blue nevi. Congenital nevi are present at birth or within a few months and often have unique features, including perifollicular pigmentary changes, hypertrichosis, and focal hypopigmentation. Acquired nevi (blue nevi, benign melanocytic nevi, and atypical or dysplastic nevi) usually descend over time from the dermal-epidermal junction to the dermis and typically become a lighter color. Lastly, the presence or absence of background pigmentation can help distinguish between agminated blue nevi and nevus spilus. Nevus spilus is a subtype of congenital melanocytic nevi with a similar aggregated appearance but has a characteristic background hyperpigmentation between the discrete nevi.

Agminated blue nevi and nevus spilus can be differentiated in the clinic by using a Wood’s lamp or performing a biopsy, which is not indicated unless atypia is present. If a non-speckled background hyperpigmentation is present on Wood’s lamp illumination, the diagnosis of nevus spilus may be more appropriate, as agminated blue nevi typically show no background pigmentation. A biopsy of the skin would allow for distinguishing between nevus spilus and agminated nevi based on the pigment within the surrounding skin. The presence of melanocytic hyperplasia within the skin surrounding the discrete nevi would support the diagnosis of nevus spilus.

The main concern with any melanocytic proliferation is the potential for transformation into a melanoma. In general, agminated nevi carry an increased melanoma risk. Specifically, congenital melanocytic nevi result in a <1-5% risk of melanoma depending on the lesion size. The risk of melanoma associated with agminated blue nevi is currently unknown, but it should be noted that individual blue nevi rarely become malignant. Since more than 50% of cutaneous melanomas develop without a preceding nevus, removal of nevi to reduce melanoma risk is not typically indicated, except in the case of a large congenital melanocytic nevi (>20cm). However, long-term surveillance is crucial for agminated blue nevi, especially if the individual has dysplastic nevus syndrome. If the involved nevi develop any features of atypia, a biopsy should be performed to assess for the development of a melanoma.

This case and photo were submitted by Dr. Damon McClain of Three Rivers Dermatology in Coraopolis, Pa., and Mark Ash, a medical student at East Carolina University, Greenville, N.C. 

Dr. Bilu Martin is in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit your case for possible publication, send an email to [email protected].

References:

1. Ashfaq A. Marghoob, Robin Blum, Robert Nossa, Klaus J. Busam, Dana Sachs, Allan Halpern. Agminated Atypical (Dysplastic) Nevi Case Report and Review of the Literature. Arch Dermatol. 2001;137(7):917-920.
2. Belinda Tan, Noah Craft, Lindy P. Fox, Lowell A. Goldsmith, Michael D. Tharp. Visual Dx. Blue Nevus. Accessed 2/11/16. Camila Roos Mariano da Rocha, Thaís Corsetti Grazziotin, Maria Carolina Widholzer Rey, Laura Luzzatto, Renan Rangel Bonamigo. Congenital agminated melanocytic nevus - Case report. An Bras Dermatol. 2013;88(6 Suppl 1):170-2.
3. Chris G. Adigun, Jeffrey D. Bernhard, Sarah Stein, Karen Wiss, Sheila Galbraith, Craig N. Burkhart, Dean Morrell, Lynn Garfunkel, Nancy Esterly. Visual Dx. Agminated Nevus. Accessed 2/11/16.
4. Julie V Schaffer and Jean L Bolognia. Acquired melanocytic nevi (moles). In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on February 11, 2016.)
5. Julie V Schaffer and Jean L Bolognia. Congenital melanocytic nevi. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on February 11, 2016.)
6. Maria A. Pizzichetta, H. Peter Soyer, Cesare Massone, Lorenzo Cerroni. Clinical and Dermoscopic Features of Agminated Blue Nevus. Arch Dermatol. 2007;143(9):1209-1226.

Nikesh Ardeshna, MD

Dr. Ardeshna is the Medical Director of Adult Epilepsy Services at Royal Oak Hospital, Beaumont Health System, in Royal Oak, Michigan.

The patient is a 74-year-old male diagnosed with primary generalized epilepsy since age 35. The patient’s last grand mal seizure was 15 years ago. He was referred to an epileptologist for establishment of care, as his current neurologist was retiring. The patient was accompanied by his family. The patient indicated that he was seizure free. His antiepileptic regimen included levetiracetam (Keppra) 2000 mg twice daily, primidone (Mysoline) 500 mg twice daily, phenytoin (Dilantin) 300 mg twice daily, and topiramate (Topamax) 300 mg twice daily. When taking the inital history, the epileptologist noticed the patient’s attention and concentration waxed and waned. Instructions had to be repeated and items re-explained. His rate of processing was slow and there were pauses in his speech. On mental status testing, registration was three out of three items; recall after delay was one out of three. The physical examination revealed a wide based gait. Swelling of the gums was noted (the patient mentioned that his dentist told him that his gums bleed easily). The patient showed the epileptologist the report of his recent bone scan, demonstrating significant osteopenia, and asked if a cause for that could be determined. Though the patient did not admit it, his family indicated that the patient’s short-term memory was essentially “non-existent” and his walking also had become quite unstable. All of these observations have been happening for the last few years.

Questions:

1.       Was the patient seizure free?

Possibly yes, possibly no. Based on the examination: the patient has pauses in his speech and slowed processing. The differential diagnosis includes seizures. Some of the patient’s presentation may be due to the side effects of antiepileptic drugs (AEDs). It is also possible that the patient’s presentation was due to a combination of seizures and side effects of AEDs.

2.       What are some of the side effects of AEDs the patient is taking?

Cognitive slowing, memory loss, slowed processing, word-finding difficulties, mood changes, osteopenia, gait instability, dizziness, and gingival hyperplasia.

3.       Based on the patient’s age, medical conditions, and exam what if any changes should be considered to the antiepileptic regimen?

a.       Simplify the regimen, if possible to 3 or fewer AEDs. Polytherapy can lead to more side effects.

b.      Based on the patient’s complaining of bleeding gums, and family indicating he walks unsteady, consideration could be given to tapering phenytoin and increasing one of the other AEDs, or substituting the phenytoin for another AED. The overall goal would be to simplify the patient’s AED regimen, and/or use newer agents with comparatively lesser likelihood of side effects that are less likely to interact with other AEDs or medications. 

Nikesh Ardeshna, MD

Dr. Ardeshna is the Medical Director of Adult Epilepsy Services at Royal Oak Hospital, Beaumont Health System, in Royal Oak, Michigan.

The patient is a 74-year-old male diagnosed with primary generalized epilepsy since age 35. The patient’s last grand mal seizure was 15 years ago. He was referred to an epileptologist for establishment of care, as his current neurologist was retiring. The patient was accompanied by his family. The patient indicated that he was seizure free. His antiepileptic regimen included levetiracetam (Keppra) 2000 mg twice daily, primidone (Mysoline) 500 mg twice daily, phenytoin (Dilantin) 300 mg twice daily, and topiramate (Topamax) 300 mg twice daily. When taking the inital history, the epileptologist noticed the patient’s attention and concentration waxed and waned. Instructions had to be repeated and items re-explained. His rate of processing was slow and there were pauses in his speech. On mental status testing, registration was three out of three items; recall after delay was one out of three. The physical examination revealed a wide based gait. Swelling of the gums was noted (the patient mentioned that his dentist told him that his gums bleed easily). The patient showed the epileptologist the report of his recent bone scan, demonstrating significant osteopenia, and asked if a cause for that could be determined. Though the patient did not admit it, his family indicated that the patient’s short-term memory was essentially “non-existent” and his walking also had become quite unstable. All of these observations have been happening for the last few years.

Questions:

1.       Was the patient seizure free?

Possibly yes, possibly no. Based on the examination: the patient has pauses in his speech and slowed processing. The differential diagnosis includes seizures. Some of the patient’s presentation may be due to the side effects of antiepileptic drugs (AEDs). It is also possible that the patient’s presentation was due to a combination of seizures and side effects of AEDs.

2.       What are some of the side effects of AEDs the patient is taking?

Cognitive slowing, memory loss, slowed processing, word-finding difficulties, mood changes, osteopenia, gait instability, dizziness, and gingival hyperplasia.

3.       Based on the patient’s age, medical conditions, and exam what if any changes should be considered to the antiepileptic regimen?

a.       Simplify the regimen, if possible to 3 or fewer AEDs. Polytherapy can lead to more side effects.

b.      Based on the patient’s complaining of bleeding gums, and family indicating he walks unsteady, consideration could be given to tapering phenytoin and increasing one of the other AEDs, or substituting the phenytoin for another AED. The overall goal would be to simplify the patient’s AED regimen, and/or use newer agents with comparatively lesser likelihood of side effects that are less likely to interact with other AEDs or medications. 

Nikesh Ardeshna, MD

Dr. Ardeshna is the Medical Director of Adult Epilepsy Services at Royal Oak Hospital, Beaumont Health System, in Royal Oak, Michigan.

The patient is a 74-year-old male diagnosed with primary generalized epilepsy since age 35. The patient’s last grand mal seizure was 15 years ago. He was referred to an epileptologist for establishment of care, as his current neurologist was retiring. The patient was accompanied by his family. The patient indicated that he was seizure free. His antiepileptic regimen included levetiracetam (Keppra) 2000 mg twice daily, primidone (Mysoline) 500 mg twice daily, phenytoin (Dilantin) 300 mg twice daily, and topiramate (Topamax) 300 mg twice daily. When taking the inital history, the epileptologist noticed the patient’s attention and concentration waxed and waned. Instructions had to be repeated and items re-explained. His rate of processing was slow and there were pauses in his speech. On mental status testing, registration was three out of three items; recall after delay was one out of three. The physical examination revealed a wide based gait. Swelling of the gums was noted (the patient mentioned that his dentist told him that his gums bleed easily). The patient showed the epileptologist the report of his recent bone scan, demonstrating significant osteopenia, and asked if a cause for that could be determined. Though the patient did not admit it, his family indicated that the patient’s short-term memory was essentially “non-existent” and his walking also had become quite unstable. All of these observations have been happening for the last few years.

Questions:

1.       Was the patient seizure free?

Possibly yes, possibly no. Based on the examination: the patient has pauses in his speech and slowed processing. The differential diagnosis includes seizures. Some of the patient’s presentation may be due to the side effects of antiepileptic drugs (AEDs). It is also possible that the patient’s presentation was due to a combination of seizures and side effects of AEDs.

2.       What are some of the side effects of AEDs the patient is taking?

Cognitive slowing, memory loss, slowed processing, word-finding difficulties, mood changes, osteopenia, gait instability, dizziness, and gingival hyperplasia.

3.       Based on the patient’s age, medical conditions, and exam what if any changes should be considered to the antiepileptic regimen?

a.       Simplify the regimen, if possible to 3 or fewer AEDs. Polytherapy can lead to more side effects.

b.      Based on the patient’s complaining of bleeding gums, and family indicating he walks unsteady, consideration could be given to tapering phenytoin and increasing one of the other AEDs, or substituting the phenytoin for another AED. The overall goal would be to simplify the patient’s AED regimen, and/or use newer agents with comparatively lesser likelihood of side effects that are less likely to interact with other AEDs or medications. 

DENVER – Long-term continuous positive airway pressure (CPAP) for treatment of sleep apnea in patients with a recent mild stroke or transient ischemic attack resulted in improved cardiovascular and metabolic risk factors, better neurologic function, and a reduction in the recurrent vascular event rate, compared with usual care in the SLEEP TIGHT study.

“Up to 25% of patients will have a stroke, cardiovascular event, or death within 90 days after a minor stroke or TIA [transient ischemic attack] despite current preventive strategies. And, importantly, patients with a TIA or stroke have a high prevalence of obstructive sleep apnea – on the order of 60%-80%,” explained Dr. H. Klar Yaggi at the annual meeting of the Associated Professional Sleep Societies.

SLEEP TIGHT’s findings support the hypothesis that diagnosis and treatment of sleep apnea in patients with a recent minor stroke or TIA will address a major unmet need for better methods of reducing the high vascular risk present in this population, said Dr. Yaggi of Yale University in New Haven, Conn.

SLEEP TIGHT was a National Heart, Lung, and Blood Institute–sponsored phase II, 12-month, multicenter, single-blind, randomized, proof-of-concept study. It included 252 patients, 80% of whom had a recent minor stroke, the rest a TIA. These were patients with high levels of cardiovascular risk factors: two-thirds had hypertension, half were hyperlipidemic, 40% had diabetes, 15% had a prior MI, 10% had atrial fibrillation, and the group’s mean body mass index was 30 kg/m². Polysomnography revealed that 76% of subjects had sleep apnea as defined by an apnea-hypopnea index of at least 5 events per hour. In fact, they averaged about 23 events per hour, putting them in the moderate-severity range. As is common among stroke/TIA patients with sleep apnea, they experienced less daytime sleepiness than is typical in a sleep clinic population, with a mean baseline Epworth Sleepiness Scale score of 7.

Participants were randomized to one of three groups: a usual care control group, a CPAP arm, or an enhanced CPAP arm. The enhanced intervention protocol was designed to boost CPAP adherence; it included targeted education, a customized cognitive intervention, and additional CPAP support beyond the standard CPAP protocols used in sleep medicine clinics. Patients with sleep apnea in the two intervention arms were then placed on CPAP.

At 1 year of follow-up, the stroke rate was 8.7 per 100 patient-years in the usual care group, compared with 5.5 per 100 person-years in the combined intervention arms. The composite cardiovascular event rate, composed of all-cause mortality, acute MI, stroke, hospitalization for unstable angina, or urgent coronary revascularization, was 13.1 per 100 person-years with usual care and 11.0 in the CPAP intervention arms. While these results are encouraging, SLEEP TIGHT wasn’t powered to show significant differences in these hard events.

Outcomes across the board didn’t differ significantly between the CPAP and enhanced CPAP groups. And since the mean number of hours of CPAP use per night was also similar in the two groups – 3.9 hours with standard CPAP and 4.3 hours with enhanced CPAP – it’s likely that the phase III trial will rely upon the much simpler standard CPAP intervention, according to Dr. Yaggi.

He deemed CPAP adherence in this stroke/TIA population to be similar to the rates typically seen in routine sleep medicine practice. Roughly 40% of the stroke/TIA patients were rated as having good adherence, 30% made some use of the therapy, and 30% had no or poor adherence.

Nonetheless, patients in the two intervention arms did significantly better than the usual care group in terms of 1-year changes in insulin resistance and glycosylated hemoglobin. They also had lower 24-hour mean systolic blood pressure and were more likely to convert to a favorable pattern of nocturnal blood pressure dipping. However, no differences between the intervention and usual care groups were seen in levels of high-sensitivity C-reactive protein and interleukin-6, the two markers of systemic inflammation analyzed. Nor did the CPAP intervention provide any benefit in terms of heart rate variability and other measures of autonomic function.

Fifty-eight percent of patients in the intervention arms ended up with a desirable National Institutes of Health Stroke Scale score of 0-1, compared with 38% of the usual care group. In addition, daytime sleepiness as reflected in Epworth Sleepiness Scale scores was reduced at last follow-up to a significantly greater extent in the CPAP groups, Dr. Yaggi noted.

Greater CPAP use was associated with a favorable trend for improvement in the modified Rankin score, a measure of functional ability: a 0.3-point reduction with no or poor CPAP use, a 0.4-point decrease with some use, and a 0.9-point reduction with good use.

The encouraging results will be helpful in designing a planned much larger, event-driven, definitive phase III trial, Dr. Yaggi said.

Dr. Yaggi reported having no financial conflicts regarding this National Heart, Lung and Blood Institute-sponsored study.

[email protected]

DENVER – Long-term continuous positive airway pressure (CPAP) for treatment of sleep apnea in patients with a recent mild stroke or transient ischemic attack resulted in improved cardiovascular and metabolic risk factors, better neurologic function, and a reduction in the recurrent vascular event rate, compared with usual care in the SLEEP TIGHT study.

“Up to 25% of patients will have a stroke, cardiovascular event, or death within 90 days after a minor stroke or TIA [transient ischemic attack] despite current preventive strategies. And, importantly, patients with a TIA or stroke have a high prevalence of obstructive sleep apnea – on the order of 60%-80%,” explained Dr. H. Klar Yaggi at the annual meeting of the Associated Professional Sleep Societies.

SLEEP TIGHT’s findings support the hypothesis that diagnosis and treatment of sleep apnea in patients with a recent minor stroke or TIA will address a major unmet need for better methods of reducing the high vascular risk present in this population, said Dr. Yaggi of Yale University in New Haven, Conn.

SLEEP TIGHT was a National Heart, Lung, and Blood Institute–sponsored phase II, 12-month, multicenter, single-blind, randomized, proof-of-concept study. It included 252 patients, 80% of whom had a recent minor stroke, the rest a TIA. These were patients with high levels of cardiovascular risk factors: two-thirds had hypertension, half were hyperlipidemic, 40% had diabetes, 15% had a prior MI, 10% had atrial fibrillation, and the group’s mean body mass index was 30 kg/m². Polysomnography revealed that 76% of subjects had sleep apnea as defined by an apnea-hypopnea index of at least 5 events per hour. In fact, they averaged about 23 events per hour, putting them in the moderate-severity range. As is common among stroke/TIA patients with sleep apnea, they experienced less daytime sleepiness than is typical in a sleep clinic population, with a mean baseline Epworth Sleepiness Scale score of 7.

Participants were randomized to one of three groups: a usual care control group, a CPAP arm, or an enhanced CPAP arm. The enhanced intervention protocol was designed to boost CPAP adherence; it included targeted education, a customized cognitive intervention, and additional CPAP support beyond the standard CPAP protocols used in sleep medicine clinics. Patients with sleep apnea in the two intervention arms were then placed on CPAP.

At 1 year of follow-up, the stroke rate was 8.7 per 100 patient-years in the usual care group, compared with 5.5 per 100 person-years in the combined intervention arms. The composite cardiovascular event rate, composed of all-cause mortality, acute MI, stroke, hospitalization for unstable angina, or urgent coronary revascularization, was 13.1 per 100 person-years with usual care and 11.0 in the CPAP intervention arms. While these results are encouraging, SLEEP TIGHT wasn’t powered to show significant differences in these hard events.

Outcomes across the board didn’t differ significantly between the CPAP and enhanced CPAP groups. And since the mean number of hours of CPAP use per night was also similar in the two groups – 3.9 hours with standard CPAP and 4.3 hours with enhanced CPAP – it’s likely that the phase III trial will rely upon the much simpler standard CPAP intervention, according to Dr. Yaggi.

He deemed CPAP adherence in this stroke/TIA population to be similar to the rates typically seen in routine sleep medicine practice. Roughly 40% of the stroke/TIA patients were rated as having good adherence, 30% made some use of the therapy, and 30% had no or poor adherence.

Nonetheless, patients in the two intervention arms did significantly better than the usual care group in terms of 1-year changes in insulin resistance and glycosylated hemoglobin. They also had lower 24-hour mean systolic blood pressure and were more likely to convert to a favorable pattern of nocturnal blood pressure dipping. However, no differences between the intervention and usual care groups were seen in levels of high-sensitivity C-reactive protein and interleukin-6, the two markers of systemic inflammation analyzed. Nor did the CPAP intervention provide any benefit in terms of heart rate variability and other measures of autonomic function.

Fifty-eight percent of patients in the intervention arms ended up with a desirable National Institutes of Health Stroke Scale score of 0-1, compared with 38% of the usual care group. In addition, daytime sleepiness as reflected in Epworth Sleepiness Scale scores was reduced at last follow-up to a significantly greater extent in the CPAP groups, Dr. Yaggi noted.

Greater CPAP use was associated with a favorable trend for improvement in the modified Rankin score, a measure of functional ability: a 0.3-point reduction with no or poor CPAP use, a 0.4-point decrease with some use, and a 0.9-point reduction with good use.

The encouraging results will be helpful in designing a planned much larger, event-driven, definitive phase III trial, Dr. Yaggi said.

Dr. Yaggi reported having no financial conflicts regarding this National Heart, Lung and Blood Institute-sponsored study.

[email protected]

DENVER – Long-term continuous positive airway pressure (CPAP) for treatment of sleep apnea in patients with a recent mild stroke or transient ischemic attack resulted in improved cardiovascular and metabolic risk factors, better neurologic function, and a reduction in the recurrent vascular event rate, compared with usual care in the SLEEP TIGHT study.

“Up to 25% of patients will have a stroke, cardiovascular event, or death within 90 days after a minor stroke or TIA [transient ischemic attack] despite current preventive strategies. And, importantly, patients with a TIA or stroke have a high prevalence of obstructive sleep apnea – on the order of 60%-80%,” explained Dr. H. Klar Yaggi at the annual meeting of the Associated Professional Sleep Societies.

SLEEP TIGHT’s findings support the hypothesis that diagnosis and treatment of sleep apnea in patients with a recent minor stroke or TIA will address a major unmet need for better methods of reducing the high vascular risk present in this population, said Dr. Yaggi of Yale University in New Haven, Conn.

SLEEP TIGHT was a National Heart, Lung, and Blood Institute–sponsored phase II, 12-month, multicenter, single-blind, randomized, proof-of-concept study. It included 252 patients, 80% of whom had a recent minor stroke, the rest a TIA. These were patients with high levels of cardiovascular risk factors: two-thirds had hypertension, half were hyperlipidemic, 40% had diabetes, 15% had a prior MI, 10% had atrial fibrillation, and the group’s mean body mass index was 30 kg/m². Polysomnography revealed that 76% of subjects had sleep apnea as defined by an apnea-hypopnea index of at least 5 events per hour. In fact, they averaged about 23 events per hour, putting them in the moderate-severity range. As is common among stroke/TIA patients with sleep apnea, they experienced less daytime sleepiness than is typical in a sleep clinic population, with a mean baseline Epworth Sleepiness Scale score of 7.

Participants were randomized to one of three groups: a usual care control group, a CPAP arm, or an enhanced CPAP arm. The enhanced intervention protocol was designed to boost CPAP adherence; it included targeted education, a customized cognitive intervention, and additional CPAP support beyond the standard CPAP protocols used in sleep medicine clinics. Patients with sleep apnea in the two intervention arms were then placed on CPAP.

At 1 year of follow-up, the stroke rate was 8.7 per 100 patient-years in the usual care group, compared with 5.5 per 100 person-years in the combined intervention arms. The composite cardiovascular event rate, composed of all-cause mortality, acute MI, stroke, hospitalization for unstable angina, or urgent coronary revascularization, was 13.1 per 100 person-years with usual care and 11.0 in the CPAP intervention arms. While these results are encouraging, SLEEP TIGHT wasn’t powered to show significant differences in these hard events.

Outcomes across the board didn’t differ significantly between the CPAP and enhanced CPAP groups. And since the mean number of hours of CPAP use per night was also similar in the two groups – 3.9 hours with standard CPAP and 4.3 hours with enhanced CPAP – it’s likely that the phase III trial will rely upon the much simpler standard CPAP intervention, according to Dr. Yaggi.

He deemed CPAP adherence in this stroke/TIA population to be similar to the rates typically seen in routine sleep medicine practice. Roughly 40% of the stroke/TIA patients were rated as having good adherence, 30% made some use of the therapy, and 30% had no or poor adherence.

Nonetheless, patients in the two intervention arms did significantly better than the usual care group in terms of 1-year changes in insulin resistance and glycosylated hemoglobin. They also had lower 24-hour mean systolic blood pressure and were more likely to convert to a favorable pattern of nocturnal blood pressure dipping. However, no differences between the intervention and usual care groups were seen in levels of high-sensitivity C-reactive protein and interleukin-6, the two markers of systemic inflammation analyzed. Nor did the CPAP intervention provide any benefit in terms of heart rate variability and other measures of autonomic function.

Fifty-eight percent of patients in the intervention arms ended up with a desirable National Institutes of Health Stroke Scale score of 0-1, compared with 38% of the usual care group. In addition, daytime sleepiness as reflected in Epworth Sleepiness Scale scores was reduced at last follow-up to a significantly greater extent in the CPAP groups, Dr. Yaggi noted.

Greater CPAP use was associated with a favorable trend for improvement in the modified Rankin score, a measure of functional ability: a 0.3-point reduction with no or poor CPAP use, a 0.4-point decrease with some use, and a 0.9-point reduction with good use.

The encouraging results will be helpful in designing a planned much larger, event-driven, definitive phase III trial, Dr. Yaggi said.

Dr. Yaggi reported having no financial conflicts regarding this National Heart, Lung and Blood Institute-sponsored study.

[email protected]

CHICAGO – The novel combination of everolimus, letrozole, and metformin was associated with improved clinical benefit and objective response rates, compared with everolimus and letrozole without metformin in patients with advanced or recurrent, previously treated endometrioid endometrial cancer (EEC) in an ongoing open-label, single-arm, prospective phase II study.

Frontline Medical News

In 49 patients with an evaluable response to the combination therapy, 29 (60%) derived clinical benefit – defined as complete response, partial response, or stable disease confirmed at 8 weeks by RECIST 1.1, Dr. Pamela T. Soliman reported at the annual meeting of the American Society of Clinical Oncology.

The best overall response to date was 29% partial response and 31% stable disease (60% clinical benefit rate) with a median of six cycles, said Dr. Soliman of the University of Texas MD Anderson Cancer Center, Houston.

So far, 58 patients have been enrolled in the study, and 194 cycles have been completed. Eight patients have received more than 14 cycles, and of those, 6 have achieved a partial response and 2 have stable disease.

Eight remain on active treatment.

“Of note, at the time of first assessment at 8 weeks, the objective response rate was only 14%, so over half of the responses were seen after at least 4 cycles of therapy were administered,” she said.

Endometrial cancer is the most common gynecologic malignancy, with an estimated 52,000 cases to be diagnosed this year. Most cases are diagnosed early, and the overall prognosis is good; the 5-year survival rate is nearly 90%.

“Unfortunately, for those women who recur, treatment options are limited,” Dr. Soliman said, noting that the best response rate seen in studies of various single and combination chemotherapy agents has been about 25% – occurring with paclitaxel and with bevacizumab-temsirolimus.

The novel combination therapy used in the current study was developed based on prior studies, including one conducted by Dr. Soliman and her colleagues, showing promising results with combination everolimus and letrozole for recurrent EEC. The investigators found that in one study of 35 patients on the everolimus and letrozole regimen, the overall response rate was 23%, the clinical benefit rate was 38%, and progression-free survival was 1.9 months, but they noticed that in a subgroup of patients who had received metformin during the course of the study, the corresponding rates were 56%, 78%, and 14 months. Preclinical data suggested that the benefit of adding metformin to the combination was particularly pronounced in patients with KRAS mutation. The current study was designed to evaluate this approach.

Study subjects had advanced/recurrent EEC and up to two prior chemotherapy regimens for recurrence. Molecular testing was performed to determine KRAS mutation status.

A pretreatment biopsy was performed for histological confirmation and molecular analysis, followed by a 1 week metformin lead in and then treatment with 10 mg oral everolimus daily, 2.5 mg or oral letrozole daily, and 500 mg of oral metformin twice daily. A single dose reduction of everolimus was permitted, and patients were treated until their disease progressed or until they experienced toxicity. Response was evaluated by imaging at 8 weeks or after 2 cycles of therapy, and confirmation of response was performed at 16 weeks, or after 4 cycles of therapy.

In this preliminary evaluation, no significant difference was seen in the clinical benefit rate based on KRAS mutation status (67% in 15 patients with KRAS mutation, 77% in 26 patients without the mutation), but further correlation between molecular findings and response are currently being evaluated.

The most common side effects were diarrhea, anemia, fatigue, nausea, mucositis, hypertriglyceridemia, and elevated aspartate aminotransferase, Dr. Soliman said, noting that 43% of patients experienced a grade 3/4 toxicity, 4 required a dose reduction, and 2 withdrew from the study.

Additionally, one patient with a partial response after 1 cycle was removed from treatment due to increased liver enzymes.

A comparison with findings from the prior everolimus and letrozole study showed that metformin did not add significant toxicity to the regimen, she noted.

“The addition of metformin to the everolimus and letrozole backbone, increased the clinical benefit rate from 40% to 60%. Overall the toxicity of all three drugs was manageable and few patients came off study due to toxicity ... Based on these findings and other studies, the use of targeted therapy in women with recurrent endometrial endometrioid cancer appears to benefit patients over standard cytotoxic chemotherapy,” Dr. Soliman concluded, adding that further development of this combination for use in patients with EEC is warranted.

She noted that an ongoing randomized clinical trial – GOG 3007 – is comparing everolimus and letrozole with tamoxifen alternating with megestrol acetate.

“This trial has recently completed accrual and results are pending. This will allow us to better identify how this treatment strategy compares to hormonal therapy alone in women with recurrent endometrial cancer. In addition, at our institution we are investigating other agents to be added to the everolimus and letrozole backbone to enhance response to patients with endometrioid endometrial cancer,” she said.

Dr. Soliman reported receiving research funding (to her institution) from Novartis.

[email protected]

CHICAGO – The novel combination of everolimus, letrozole, and metformin was associated with improved clinical benefit and objective response rates, compared with everolimus and letrozole without metformin in patients with advanced or recurrent, previously treated endometrioid endometrial cancer (EEC) in an ongoing open-label, single-arm, prospective phase II study.

Frontline Medical News

In 49 patients with an evaluable response to the combination therapy, 29 (60%) derived clinical benefit – defined as complete response, partial response, or stable disease confirmed at 8 weeks by RECIST 1.1, Dr. Pamela T. Soliman reported at the annual meeting of the American Society of Clinical Oncology.

The best overall response to date was 29% partial response and 31% stable disease (60% clinical benefit rate) with a median of six cycles, said Dr. Soliman of the University of Texas MD Anderson Cancer Center, Houston.

So far, 58 patients have been enrolled in the study, and 194 cycles have been completed. Eight patients have received more than 14 cycles, and of those, 6 have achieved a partial response and 2 have stable disease.

Eight remain on active treatment.

“Of note, at the time of first assessment at 8 weeks, the objective response rate was only 14%, so over half of the responses were seen after at least 4 cycles of therapy were administered,” she said.

Endometrial cancer is the most common gynecologic malignancy, with an estimated 52,000 cases to be diagnosed this year. Most cases are diagnosed early, and the overall prognosis is good; the 5-year survival rate is nearly 90%.

“Unfortunately, for those women who recur, treatment options are limited,” Dr. Soliman said, noting that the best response rate seen in studies of various single and combination chemotherapy agents has been about 25% – occurring with paclitaxel and with bevacizumab-temsirolimus.

The novel combination therapy used in the current study was developed based on prior studies, including one conducted by Dr. Soliman and her colleagues, showing promising results with combination everolimus and letrozole for recurrent EEC. The investigators found that in one study of 35 patients on the everolimus and letrozole regimen, the overall response rate was 23%, the clinical benefit rate was 38%, and progression-free survival was 1.9 months, but they noticed that in a subgroup of patients who had received metformin during the course of the study, the corresponding rates were 56%, 78%, and 14 months. Preclinical data suggested that the benefit of adding metformin to the combination was particularly pronounced in patients with KRAS mutation. The current study was designed to evaluate this approach.

Study subjects had advanced/recurrent EEC and up to two prior chemotherapy regimens for recurrence. Molecular testing was performed to determine KRAS mutation status.

A pretreatment biopsy was performed for histological confirmation and molecular analysis, followed by a 1 week metformin lead in and then treatment with 10 mg oral everolimus daily, 2.5 mg or oral letrozole daily, and 500 mg of oral metformin twice daily. A single dose reduction of everolimus was permitted, and patients were treated until their disease progressed or until they experienced toxicity. Response was evaluated by imaging at 8 weeks or after 2 cycles of therapy, and confirmation of response was performed at 16 weeks, or after 4 cycles of therapy.

In this preliminary evaluation, no significant difference was seen in the clinical benefit rate based on KRAS mutation status (67% in 15 patients with KRAS mutation, 77% in 26 patients without the mutation), but further correlation between molecular findings and response are currently being evaluated.

The most common side effects were diarrhea, anemia, fatigue, nausea, mucositis, hypertriglyceridemia, and elevated aspartate aminotransferase, Dr. Soliman said, noting that 43% of patients experienced a grade 3/4 toxicity, 4 required a dose reduction, and 2 withdrew from the study.

Additionally, one patient with a partial response after 1 cycle was removed from treatment due to increased liver enzymes.

A comparison with findings from the prior everolimus and letrozole study showed that metformin did not add significant toxicity to the regimen, she noted.

“The addition of metformin to the everolimus and letrozole backbone, increased the clinical benefit rate from 40% to 60%. Overall the toxicity of all three drugs was manageable and few patients came off study due to toxicity ... Based on these findings and other studies, the use of targeted therapy in women with recurrent endometrial endometrioid cancer appears to benefit patients over standard cytotoxic chemotherapy,” Dr. Soliman concluded, adding that further development of this combination for use in patients with EEC is warranted.

She noted that an ongoing randomized clinical trial – GOG 3007 – is comparing everolimus and letrozole with tamoxifen alternating with megestrol acetate.

“This trial has recently completed accrual and results are pending. This will allow us to better identify how this treatment strategy compares to hormonal therapy alone in women with recurrent endometrial cancer. In addition, at our institution we are investigating other agents to be added to the everolimus and letrozole backbone to enhance response to patients with endometrioid endometrial cancer,” she said.

Dr. Soliman reported receiving research funding (to her institution) from Novartis.

[email protected]

CHICAGO – The novel combination of everolimus, letrozole, and metformin was associated with improved clinical benefit and objective response rates, compared with everolimus and letrozole without metformin in patients with advanced or recurrent, previously treated endometrioid endometrial cancer (EEC) in an ongoing open-label, single-arm, prospective phase II study.

Frontline Medical News

In 49 patients with an evaluable response to the combination therapy, 29 (60%) derived clinical benefit – defined as complete response, partial response, or stable disease confirmed at 8 weeks by RECIST 1.1, Dr. Pamela T. Soliman reported at the annual meeting of the American Society of Clinical Oncology.

The best overall response to date was 29% partial response and 31% stable disease (60% clinical benefit rate) with a median of six cycles, said Dr. Soliman of the University of Texas MD Anderson Cancer Center, Houston.

So far, 58 patients have been enrolled in the study, and 194 cycles have been completed. Eight patients have received more than 14 cycles, and of those, 6 have achieved a partial response and 2 have stable disease.

Eight remain on active treatment.

“Of note, at the time of first assessment at 8 weeks, the objective response rate was only 14%, so over half of the responses were seen after at least 4 cycles of therapy were administered,” she said.

Endometrial cancer is the most common gynecologic malignancy, with an estimated 52,000 cases to be diagnosed this year. Most cases are diagnosed early, and the overall prognosis is good; the 5-year survival rate is nearly 90%.

“Unfortunately, for those women who recur, treatment options are limited,” Dr. Soliman said, noting that the best response rate seen in studies of various single and combination chemotherapy agents has been about 25% – occurring with paclitaxel and with bevacizumab-temsirolimus.

The novel combination therapy used in the current study was developed based on prior studies, including one conducted by Dr. Soliman and her colleagues, showing promising results with combination everolimus and letrozole for recurrent EEC. The investigators found that in one study of 35 patients on the everolimus and letrozole regimen, the overall response rate was 23%, the clinical benefit rate was 38%, and progression-free survival was 1.9 months, but they noticed that in a subgroup of patients who had received metformin during the course of the study, the corresponding rates were 56%, 78%, and 14 months. Preclinical data suggested that the benefit of adding metformin to the combination was particularly pronounced in patients with KRAS mutation. The current study was designed to evaluate this approach.

Study subjects had advanced/recurrent EEC and up to two prior chemotherapy regimens for recurrence. Molecular testing was performed to determine KRAS mutation status.

A pretreatment biopsy was performed for histological confirmation and molecular analysis, followed by a 1 week metformin lead in and then treatment with 10 mg oral everolimus daily, 2.5 mg or oral letrozole daily, and 500 mg of oral metformin twice daily. A single dose reduction of everolimus was permitted, and patients were treated until their disease progressed or until they experienced toxicity. Response was evaluated by imaging at 8 weeks or after 2 cycles of therapy, and confirmation of response was performed at 16 weeks, or after 4 cycles of therapy.

In this preliminary evaluation, no significant difference was seen in the clinical benefit rate based on KRAS mutation status (67% in 15 patients with KRAS mutation, 77% in 26 patients without the mutation), but further correlation between molecular findings and response are currently being evaluated.

The most common side effects were diarrhea, anemia, fatigue, nausea, mucositis, hypertriglyceridemia, and elevated aspartate aminotransferase, Dr. Soliman said, noting that 43% of patients experienced a grade 3/4 toxicity, 4 required a dose reduction, and 2 withdrew from the study.

Additionally, one patient with a partial response after 1 cycle was removed from treatment due to increased liver enzymes.

A comparison with findings from the prior everolimus and letrozole study showed that metformin did not add significant toxicity to the regimen, she noted.

“The addition of metformin to the everolimus and letrozole backbone, increased the clinical benefit rate from 40% to 60%. Overall the toxicity of all three drugs was manageable and few patients came off study due to toxicity ... Based on these findings and other studies, the use of targeted therapy in women with recurrent endometrial endometrioid cancer appears to benefit patients over standard cytotoxic chemotherapy,” Dr. Soliman concluded, adding that further development of this combination for use in patients with EEC is warranted.

She noted that an ongoing randomized clinical trial – GOG 3007 – is comparing everolimus and letrozole with tamoxifen alternating with megestrol acetate.

“This trial has recently completed accrual and results are pending. This will allow us to better identify how this treatment strategy compares to hormonal therapy alone in women with recurrent endometrial cancer. In addition, at our institution we are investigating other agents to be added to the everolimus and letrozole backbone to enhance response to patients with endometrioid endometrial cancer,” she said.

Dr. Soliman reported receiving research funding (to her institution) from Novartis.

[email protected]

Clinical question: What are the effects of implementing standardized clinical pathways on length of stay, cost, readmissions, and patient quality of life?

Background: As payment models shift from volume- to value-based models, standardized clinical pathways are one option to simultaneously provide high-value care, improve quality, and control costs. Studies of individual clinical pathways suggest that they may be helpful in decreasing utilization, but the measured impact has varied significantly. It is unknown how much of the measured effect is due to the pathway and how much is due to the clinical factors of the disease or patient population studied. No prior studies have evaluated a suite of clinical pathways in pediatric populations.

Study design: Retrospective cohort study.

Setting: Single, 250-bed, tertiary care, freestanding children’s hospital.

Synopsis: Over four years, 15 clinical pathways were created for common pediatric medical, surgical, and psychiatric complaints (urinary tract infection, diabetes, both diabetic ketoacidosis [DKA] and non-DKA, fractures, spinal surgery, croup, neonatal jaundice, neonatal fever, depressive disorders, pyloric stenosis, pneumonia, tonsillectomy and adenoidectomy, disruptive behavior, and cellulitis/abscess).

The pathways were implemented when they were complete, with guidelines coming online throughout the study period. Implementation included an order set in the electronic medical record that included relevant literature references and decision support, online training, and integration into the clinical workflow for providers and nurses. Use of the pathways was monitored, and they were reviewed on at least a quarterly basis and revised, if necessary.

The authors examined pathway use for eligible patients, hospital costs, length of stay, 30-day readmissions, and parent-reported quality of life, both before and after pathway implementation. Patients meeting criteria for complex chronic conditions were excluded from the study.

Before implementation, 3,808 admissions fulfilled pathway criteria, and 2,902 fulfilled criteria after implementation. The pathway for depressive disorders was the most used pathway, with 411 admissions and 95% of eligible patients on the pathway. Both pyloric stenosis and neonatal jaundice had 100% pathway use.

The lowest rate of pathway use was for urinary tract infection (20%). Pathway implementation slowed the rate of rise of hospital costs. Prior to study implementation, the costs were increasing by $126 per month. Following implementation, costs decreased by $29 per month (95% CI, $100 decrease to $34 increase; P=.001). Post-implementation, the length of stay for pathway-eligible patients began a statistically significant downward trend at a rate that yielded a decrease in length of stay of 8.6 hours over a year (P=0.02). There were no differences in 30-day readmissions or parent-reported quality of life.

Bottom line: Systematic development and implementation of clinical pathways for a variety of conditions can contain costs and decrease length of stay while maintaining clinical outcomes and not increasing readmissions.

Citation: Lion KC, Wright DR, Spencer S, Zhou C, Del Beccaro M, Mangione-Smith R. Standardized clinical pathways for hospitalized children and outcomes. Pediatrics. 2016;137(4). pii:e20151202. doi:10.1542/peds.2015-1202.

Dr. Stubblefield is a pediatric hospitalist at Nemours/Alfred I. Dupont Hospital for Children in Wilmington, Del., and clinical assistant professor of pediatrics at Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia.

Clinical question: What are the effects of implementing standardized clinical pathways on length of stay, cost, readmissions, and patient quality of life?

Background: As payment models shift from volume- to value-based models, standardized clinical pathways are one option to simultaneously provide high-value care, improve quality, and control costs. Studies of individual clinical pathways suggest that they may be helpful in decreasing utilization, but the measured impact has varied significantly. It is unknown how much of the measured effect is due to the pathway and how much is due to the clinical factors of the disease or patient population studied. No prior studies have evaluated a suite of clinical pathways in pediatric populations.

Study design: Retrospective cohort study.

Setting: Single, 250-bed, tertiary care, freestanding children’s hospital.

Synopsis: Over four years, 15 clinical pathways were created for common pediatric medical, surgical, and psychiatric complaints (urinary tract infection, diabetes, both diabetic ketoacidosis [DKA] and non-DKA, fractures, spinal surgery, croup, neonatal jaundice, neonatal fever, depressive disorders, pyloric stenosis, pneumonia, tonsillectomy and adenoidectomy, disruptive behavior, and cellulitis/abscess).

The pathways were implemented when they were complete, with guidelines coming online throughout the study period. Implementation included an order set in the electronic medical record that included relevant literature references and decision support, online training, and integration into the clinical workflow for providers and nurses. Use of the pathways was monitored, and they were reviewed on at least a quarterly basis and revised, if necessary.

The authors examined pathway use for eligible patients, hospital costs, length of stay, 30-day readmissions, and parent-reported quality of life, both before and after pathway implementation. Patients meeting criteria for complex chronic conditions were excluded from the study.

Before implementation, 3,808 admissions fulfilled pathway criteria, and 2,902 fulfilled criteria after implementation. The pathway for depressive disorders was the most used pathway, with 411 admissions and 95% of eligible patients on the pathway. Both pyloric stenosis and neonatal jaundice had 100% pathway use.

The lowest rate of pathway use was for urinary tract infection (20%). Pathway implementation slowed the rate of rise of hospital costs. Prior to study implementation, the costs were increasing by $126 per month. Following implementation, costs decreased by $29 per month (95% CI, $100 decrease to $34 increase; P=.001). Post-implementation, the length of stay for pathway-eligible patients began a statistically significant downward trend at a rate that yielded a decrease in length of stay of 8.6 hours over a year (P=0.02). There were no differences in 30-day readmissions or parent-reported quality of life.

Bottom line: Systematic development and implementation of clinical pathways for a variety of conditions can contain costs and decrease length of stay while maintaining clinical outcomes and not increasing readmissions.

Citation: Lion KC, Wright DR, Spencer S, Zhou C, Del Beccaro M, Mangione-Smith R. Standardized clinical pathways for hospitalized children and outcomes. Pediatrics. 2016;137(4). pii:e20151202. doi:10.1542/peds.2015-1202.

Dr. Stubblefield is a pediatric hospitalist at Nemours/Alfred I. Dupont Hospital for Children in Wilmington, Del., and clinical assistant professor of pediatrics at Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia.

Clinical question: What are the effects of implementing standardized clinical pathways on length of stay, cost, readmissions, and patient quality of life?

Background: As payment models shift from volume- to value-based models, standardized clinical pathways are one option to simultaneously provide high-value care, improve quality, and control costs. Studies of individual clinical pathways suggest that they may be helpful in decreasing utilization, but the measured impact has varied significantly. It is unknown how much of the measured effect is due to the pathway and how much is due to the clinical factors of the disease or patient population studied. No prior studies have evaluated a suite of clinical pathways in pediatric populations.

Study design: Retrospective cohort study.

Setting: Single, 250-bed, tertiary care, freestanding children’s hospital.

Synopsis: Over four years, 15 clinical pathways were created for common pediatric medical, surgical, and psychiatric complaints (urinary tract infection, diabetes, both diabetic ketoacidosis [DKA] and non-DKA, fractures, spinal surgery, croup, neonatal jaundice, neonatal fever, depressive disorders, pyloric stenosis, pneumonia, tonsillectomy and adenoidectomy, disruptive behavior, and cellulitis/abscess).

The pathways were implemented when they were complete, with guidelines coming online throughout the study period. Implementation included an order set in the electronic medical record that included relevant literature references and decision support, online training, and integration into the clinical workflow for providers and nurses. Use of the pathways was monitored, and they were reviewed on at least a quarterly basis and revised, if necessary.

The authors examined pathway use for eligible patients, hospital costs, length of stay, 30-day readmissions, and parent-reported quality of life, both before and after pathway implementation. Patients meeting criteria for complex chronic conditions were excluded from the study.

Before implementation, 3,808 admissions fulfilled pathway criteria, and 2,902 fulfilled criteria after implementation. The pathway for depressive disorders was the most used pathway, with 411 admissions and 95% of eligible patients on the pathway. Both pyloric stenosis and neonatal jaundice had 100% pathway use.

The lowest rate of pathway use was for urinary tract infection (20%). Pathway implementation slowed the rate of rise of hospital costs. Prior to study implementation, the costs were increasing by $126 per month. Following implementation, costs decreased by $29 per month (95% CI, $100 decrease to $34 increase; P=.001). Post-implementation, the length of stay for pathway-eligible patients began a statistically significant downward trend at a rate that yielded a decrease in length of stay of 8.6 hours over a year (P=0.02). There were no differences in 30-day readmissions or parent-reported quality of life.

Bottom line: Systematic development and implementation of clinical pathways for a variety of conditions can contain costs and decrease length of stay while maintaining clinical outcomes and not increasing readmissions.

Citation: Lion KC, Wright DR, Spencer S, Zhou C, Del Beccaro M, Mangione-Smith R. Standardized clinical pathways for hospitalized children and outcomes. Pediatrics. 2016;137(4). pii:e20151202. doi:10.1542/peds.2015-1202.

Dr. Stubblefield is a pediatric hospitalist at Nemours/Alfred I. Dupont Hospital for Children in Wilmington, Del., and clinical assistant professor of pediatrics at Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia.

Attendees at ASCO 2016

© ASCO/Brian Powers

CHICAGO—Treatment dose and schedule, as well as a patient’s tumor burden, influence the outcome of therapy with chimeric antigen receptor (CAR) T cells, according to research presented at the 2016 ASCO Annual Meeting.

One presentation suggested the dose and schedule of CTL019 can impact both complete response (CR) rates and the incidence of cytokine release syndrome (CRS).

Another presentation indicated that disease burden may determine the risk of toxicity and correlate with the efficacy of JCAR015.

CTL019

Noelle Frey, MD, of the University of Pennsylvania in Philadelphia, presented results observed with CTL019 in 30 adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated on 2 trials (NCT02030847 and NCT01029366) as abstract 7002.*

Dr Frey noted that CAR T-cell therapies, including CTL019, have led to “unprecedented remission rates of between 70% and 90%.” However, immune activation that leads to high response rates also confers significant treatment-related toxicity—namely, CRS.

She reported that, in the 2 trials of adult ALL patients, a high dose of CTL019 led to a 100% response rate and a 100% CRS rate. Splitting the dose over 3 days led to an 86% response rate and a 66% CRS rate. A single low dose reduced efficacy to 33% and CRS to 66%.

Three of 6 patients who received a single high dose developed CRS and died within weeks. All of these patients had infections or sepsis that likely led to their deaths, Dr Frey said. She suggested clinicians aggressively monitor infections and treat with antimicrobials prior to CAR T-cell therapy.

“The infusion dose and schedule of CTL019 correlate with toxicity and response,” she observed. “A fractionated dosing scheme allows for real-time intra-patient dose modification in response to toxicity and the maintenance of high response rates. Concurrent sepsis and CRS confers a poor outcome.”

Dr Frey said future studies will determine the optimal approach to minimize toxicity while maintaining high efficacy. A fractionated dosing scheme is only one way to mitigate CRS. Other attractive approaches include inverse dosing based on disease burden and varying the timing of anti-cytokine-directed therapy.

JCAR015

Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York, reported data from a phase 1 clinical trial (NCT01044069) of JCAR015 in 51 adults with relapsed/refractory ALL as abstract 7003.*

Treatment with JCAR015 led to high CR rates and minimal residual disease (MRD)-negativity, regardless of the amount of disease at baseline. However, outcomes were superior among patients with minimal disease at baseline.

For patients with morphologic disease, 77% achieved a CR by 20 days after treatment, and 90% were MRD-negative.

For those with minimal disease, 90% achieved a CR by 25 days after treatment, and 78% were MRD-negative. These patients experienced significantly less CRS and neurotoxicity than patients with morphologic disease.

“High CR and MRD-negativity rates were observed regardless of pre-T-cell burden,” Dr Park noted. “We observed durable responses and survivals in a subset of patients with no subsequent allotransplant in both morphological and minimal disease cohorts.”

*Data in the abstracts differ from the presentations.

Attendees at ASCO 2016

© ASCO/Brian Powers

CHICAGO—Treatment dose and schedule, as well as a patient’s tumor burden, influence the outcome of therapy with chimeric antigen receptor (CAR) T cells, according to research presented at the 2016 ASCO Annual Meeting.

One presentation suggested the dose and schedule of CTL019 can impact both complete response (CR) rates and the incidence of cytokine release syndrome (CRS).

Another presentation indicated that disease burden may determine the risk of toxicity and correlate with the efficacy of JCAR015.

CTL019

Noelle Frey, MD, of the University of Pennsylvania in Philadelphia, presented results observed with CTL019 in 30 adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated on 2 trials (NCT02030847 and NCT01029366) as abstract 7002.*

Dr Frey noted that CAR T-cell therapies, including CTL019, have led to “unprecedented remission rates of between 70% and 90%.” However, immune activation that leads to high response rates also confers significant treatment-related toxicity—namely, CRS.

She reported that, in the 2 trials of adult ALL patients, a high dose of CTL019 led to a 100% response rate and a 100% CRS rate. Splitting the dose over 3 days led to an 86% response rate and a 66% CRS rate. A single low dose reduced efficacy to 33% and CRS to 66%.

Three of 6 patients who received a single high dose developed CRS and died within weeks. All of these patients had infections or sepsis that likely led to their deaths, Dr Frey said. She suggested clinicians aggressively monitor infections and treat with antimicrobials prior to CAR T-cell therapy.

“The infusion dose and schedule of CTL019 correlate with toxicity and response,” she observed. “A fractionated dosing scheme allows for real-time intra-patient dose modification in response to toxicity and the maintenance of high response rates. Concurrent sepsis and CRS confers a poor outcome.”

Dr Frey said future studies will determine the optimal approach to minimize toxicity while maintaining high efficacy. A fractionated dosing scheme is only one way to mitigate CRS. Other attractive approaches include inverse dosing based on disease burden and varying the timing of anti-cytokine-directed therapy.

JCAR015

Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York, reported data from a phase 1 clinical trial (NCT01044069) of JCAR015 in 51 adults with relapsed/refractory ALL as abstract 7003.*

Treatment with JCAR015 led to high CR rates and minimal residual disease (MRD)-negativity, regardless of the amount of disease at baseline. However, outcomes were superior among patients with minimal disease at baseline.

For patients with morphologic disease, 77% achieved a CR by 20 days after treatment, and 90% were MRD-negative.

For those with minimal disease, 90% achieved a CR by 25 days after treatment, and 78% were MRD-negative. These patients experienced significantly less CRS and neurotoxicity than patients with morphologic disease.

“High CR and MRD-negativity rates were observed regardless of pre-T-cell burden,” Dr Park noted. “We observed durable responses and survivals in a subset of patients with no subsequent allotransplant in both morphological and minimal disease cohorts.”

*Data in the abstracts differ from the presentations.

Attendees at ASCO 2016

© ASCO/Brian Powers

CHICAGO—Treatment dose and schedule, as well as a patient’s tumor burden, influence the outcome of therapy with chimeric antigen receptor (CAR) T cells, according to research presented at the 2016 ASCO Annual Meeting.

One presentation suggested the dose and schedule of CTL019 can impact both complete response (CR) rates and the incidence of cytokine release syndrome (CRS).

Another presentation indicated that disease burden may determine the risk of toxicity and correlate with the efficacy of JCAR015.

CTL019

Noelle Frey, MD, of the University of Pennsylvania in Philadelphia, presented results observed with CTL019 in 30 adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated on 2 trials (NCT02030847 and NCT01029366) as abstract 7002.*

Dr Frey noted that CAR T-cell therapies, including CTL019, have led to “unprecedented remission rates of between 70% and 90%.” However, immune activation that leads to high response rates also confers significant treatment-related toxicity—namely, CRS.

She reported that, in the 2 trials of adult ALL patients, a high dose of CTL019 led to a 100% response rate and a 100% CRS rate. Splitting the dose over 3 days led to an 86% response rate and a 66% CRS rate. A single low dose reduced efficacy to 33% and CRS to 66%.

Three of 6 patients who received a single high dose developed CRS and died within weeks. All of these patients had infections or sepsis that likely led to their deaths, Dr Frey said. She suggested clinicians aggressively monitor infections and treat with antimicrobials prior to CAR T-cell therapy.

“The infusion dose and schedule of CTL019 correlate with toxicity and response,” she observed. “A fractionated dosing scheme allows for real-time intra-patient dose modification in response to toxicity and the maintenance of high response rates. Concurrent sepsis and CRS confers a poor outcome.”

Dr Frey said future studies will determine the optimal approach to minimize toxicity while maintaining high efficacy. A fractionated dosing scheme is only one way to mitigate CRS. Other attractive approaches include inverse dosing based on disease burden and varying the timing of anti-cytokine-directed therapy.

JCAR015

Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York, reported data from a phase 1 clinical trial (NCT01044069) of JCAR015 in 51 adults with relapsed/refractory ALL as abstract 7003.*

Treatment with JCAR015 led to high CR rates and minimal residual disease (MRD)-negativity, regardless of the amount of disease at baseline. However, outcomes were superior among patients with minimal disease at baseline.

For patients with morphologic disease, 77% achieved a CR by 20 days after treatment, and 90% were MRD-negative.

For those with minimal disease, 90% achieved a CR by 25 days after treatment, and 78% were MRD-negative. These patients experienced significantly less CRS and neurotoxicity than patients with morphologic disease.

“High CR and MRD-negativity rates were observed regardless of pre-T-cell burden,” Dr Park noted. “We observed durable responses and survivals in a subset of patients with no subsequent allotransplant in both morphological and minimal disease cohorts.”

*Data in the abstracts differ from the presentations.

McCormick Place, site of

the ASCO Annual Meeting

© ASCO/Todd Buchanan

CHICAGO—Lenalidomide maintenance after high-dose melphalan and autologous stem cell transplant (ASCT) should be considered the standard of care in

newly diagnosed multiple myeloma (MM) patients, according to a meta-analysis presented at the 2016 ASCO Annual Meeting.

Lenalidomide maintenance increased overall survival (OS), with a 26% reduction in the risk of death, representing an estimated 2.5-year increase in median survival.

Several studies have demonstrated that lenalidomide maintenance post-ASCT reduces the risk of disease progression or death in patients with MM by about 50%.

However, these studies were not powered for OS, said Philip McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, New York.

With this in mind, Dr McCarthy and his colleagues conducted a meta-analysis to assess the effect of post-ASCT lenalidomide maintenance on OS using a pooled analysis of primary source patient data. A search revealed 17 randomized, controlled trials using lenalidomide post-ASCT.

Three trials met pre-specified inclusion criteria and had sufficient OS events to test a treatment effect. The studies intended for lenalidomide maintenance to be given until progression.

In these trials, 1209 MM patients, with a median age of 58, were randomized from 2005 to 2009 to receive lenalidomide (605 patients) at 10 mg/day on days 1-21/28 or days 1-28/28. The remaining 604 patients served as controls. Baseline characteristics were generally balanced between the 2 groups.

With a median follow-up of 6.6 years, 491 patients (41%) had died.

After induction and single (82%) or tandem (18%) ASCT, 55% of patients achieved a complete response (CR) or very good partial response.

The median OS has not been reached in the lenalidomide arm but was 86 months for the control arm.

“There is a 26% reduction in the risk of death, representing an estimated 2.5-year increase in median survival,” Dr McCarthy said.

The OS benefit favoring lenalidomide was generally consistent across the majority of subgroup analyses, including age, sex, ISS stage, response after ASCT, and prior induction therapy.

All studies contributed to the positive results of the meta-analysis. Heterogeneity tests showed significant differences across trials, mainly because of a difference in the magnitude of treatment effect, Dr McCarthy said.

The mean treatment duration of maintenance was 25 to 30 months in the lenalidomide group and 13 to 20 months in controls. About one-third to more than half of the patients received therapy for 3 or more years, Dr McCarthy said.

Lenalidomide led to an increased risk in the cumulative incidence of hematologic and solid tumor second primary malignancies. However, Dr McCarthy said the OS benefit of lenalidomide maintenance outweighs the risk of developing second primary malignancy.

“This large meta-analysis demonstrates that lenalidomide maintenance significantly prolonged OS post-ASCT, including in patients who achieved CR, demonstrating benefit in patients in all response categories,” Dr McCarthy said.

“Lenalidomide maintenance after ASCT can be considered a standard of care for newly diagnosed multiple myeloma patients. However, we have more to learn. Understanding the role of minimal residual disease detection and immune reconstitution after transplant should allow us to further improve OS. Critically, developing early endpoints as surrogates for long-term outcome and OS is important for the future. Otherwise, trials may continue for 10 years or longer.”

Dr McCarthy presented these findings as abstract 8001.

McCormick Place, site of

the ASCO Annual Meeting

© ASCO/Todd Buchanan

CHICAGO—Lenalidomide maintenance after high-dose melphalan and autologous stem cell transplant (ASCT) should be considered the standard of care in

newly diagnosed multiple myeloma (MM) patients, according to a meta-analysis presented at the 2016 ASCO Annual Meeting.

Lenalidomide maintenance increased overall survival (OS), with a 26% reduction in the risk of death, representing an estimated 2.5-year increase in median survival.

Several studies have demonstrated that lenalidomide maintenance post-ASCT reduces the risk of disease progression or death in patients with MM by about 50%.

However, these studies were not powered for OS, said Philip McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, New York.

With this in mind, Dr McCarthy and his colleagues conducted a meta-analysis to assess the effect of post-ASCT lenalidomide maintenance on OS using a pooled analysis of primary source patient data. A search revealed 17 randomized, controlled trials using lenalidomide post-ASCT.

Three trials met pre-specified inclusion criteria and had sufficient OS events to test a treatment effect. The studies intended for lenalidomide maintenance to be given until progression.

In these trials, 1209 MM patients, with a median age of 58, were randomized from 2005 to 2009 to receive lenalidomide (605 patients) at 10 mg/day on days 1-21/28 or days 1-28/28. The remaining 604 patients served as controls. Baseline characteristics were generally balanced between the 2 groups.

With a median follow-up of 6.6 years, 491 patients (41%) had died.

After induction and single (82%) or tandem (18%) ASCT, 55% of patients achieved a complete response (CR) or very good partial response.

The median OS has not been reached in the lenalidomide arm but was 86 months for the control arm.

“There is a 26% reduction in the risk of death, representing an estimated 2.5-year increase in median survival,” Dr McCarthy said.

The OS benefit favoring lenalidomide was generally consistent across the majority of subgroup analyses, including age, sex, ISS stage, response after ASCT, and prior induction therapy.

All studies contributed to the positive results of the meta-analysis. Heterogeneity tests showed significant differences across trials, mainly because of a difference in the magnitude of treatment effect, Dr McCarthy said.

The mean treatment duration of maintenance was 25 to 30 months in the lenalidomide group and 13 to 20 months in controls. About one-third to more than half of the patients received therapy for 3 or more years, Dr McCarthy said.

Lenalidomide led to an increased risk in the cumulative incidence of hematologic and solid tumor second primary malignancies. However, Dr McCarthy said the OS benefit of lenalidomide maintenance outweighs the risk of developing second primary malignancy.

“This large meta-analysis demonstrates that lenalidomide maintenance significantly prolonged OS post-ASCT, including in patients who achieved CR, demonstrating benefit in patients in all response categories,” Dr McCarthy said.

“Lenalidomide maintenance after ASCT can be considered a standard of care for newly diagnosed multiple myeloma patients. However, we have more to learn. Understanding the role of minimal residual disease detection and immune reconstitution after transplant should allow us to further improve OS. Critically, developing early endpoints as surrogates for long-term outcome and OS is important for the future. Otherwise, trials may continue for 10 years or longer.”

Dr McCarthy presented these findings as abstract 8001.

McCormick Place, site of

the ASCO Annual Meeting

© ASCO/Todd Buchanan

CHICAGO—Lenalidomide maintenance after high-dose melphalan and autologous stem cell transplant (ASCT) should be considered the standard of care in

newly diagnosed multiple myeloma (MM) patients, according to a meta-analysis presented at the 2016 ASCO Annual Meeting.

Lenalidomide maintenance increased overall survival (OS), with a 26% reduction in the risk of death, representing an estimated 2.5-year increase in median survival.

Several studies have demonstrated that lenalidomide maintenance post-ASCT reduces the risk of disease progression or death in patients with MM by about 50%.

However, these studies were not powered for OS, said Philip McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, New York.

With this in mind, Dr McCarthy and his colleagues conducted a meta-analysis to assess the effect of post-ASCT lenalidomide maintenance on OS using a pooled analysis of primary source patient data. A search revealed 17 randomized, controlled trials using lenalidomide post-ASCT.

Three trials met pre-specified inclusion criteria and had sufficient OS events to test a treatment effect. The studies intended for lenalidomide maintenance to be given until progression.

In these trials, 1209 MM patients, with a median age of 58, were randomized from 2005 to 2009 to receive lenalidomide (605 patients) at 10 mg/day on days 1-21/28 or days 1-28/28. The remaining 604 patients served as controls. Baseline characteristics were generally balanced between the 2 groups.

With a median follow-up of 6.6 years, 491 patients (41%) had died.

After induction and single (82%) or tandem (18%) ASCT, 55% of patients achieved a complete response (CR) or very good partial response.

The median OS has not been reached in the lenalidomide arm but was 86 months for the control arm.

“There is a 26% reduction in the risk of death, representing an estimated 2.5-year increase in median survival,” Dr McCarthy said.

The OS benefit favoring lenalidomide was generally consistent across the majority of subgroup analyses, including age, sex, ISS stage, response after ASCT, and prior induction therapy.

All studies contributed to the positive results of the meta-analysis. Heterogeneity tests showed significant differences across trials, mainly because of a difference in the magnitude of treatment effect, Dr McCarthy said.

The mean treatment duration of maintenance was 25 to 30 months in the lenalidomide group and 13 to 20 months in controls. About one-third to more than half of the patients received therapy for 3 or more years, Dr McCarthy said.

Lenalidomide led to an increased risk in the cumulative incidence of hematologic and solid tumor second primary malignancies. However, Dr McCarthy said the OS benefit of lenalidomide maintenance outweighs the risk of developing second primary malignancy.

“This large meta-analysis demonstrates that lenalidomide maintenance significantly prolonged OS post-ASCT, including in patients who achieved CR, demonstrating benefit in patients in all response categories,” Dr McCarthy said.

“Lenalidomide maintenance after ASCT can be considered a standard of care for newly diagnosed multiple myeloma patients. However, we have more to learn. Understanding the role of minimal residual disease detection and immune reconstitution after transplant should allow us to further improve OS. Critically, developing early endpoints as surrogates for long-term outcome and OS is important for the future. Otherwise, trials may continue for 10 years or longer.”

Dr McCarthy presented these findings as abstract 8001.