NATIONAL HARBOR, MD—Total health care costs increase following initiation of a disease-modifying therapy for multiple sclerosis (MS), but a subsequent overall decrease in health care resource utilization may partially offset the increased costs, according to data presented at the 2016 CMSC Annual Meeting. Upon initiation of disease-modifying therapy, total health care costs increase by $38,561 for patients receiving dimethyl fumarate and by $53,626 for patients receiving fingolimod.

There are limited real-world data on comparative health care resource utilization and costs associated with disease-modifying therapy use in routine clinical practice. Researchers decided to further investigate the effect of the initiation of disease-modifying therapy (ie, dimethyl fumarate, interferon β, glatiramer acetate, teriflunomide, or fingolimod) on health care resource utilization. Jacqueline Nicholas, MD, MPH, a neuroimmunologist at OhioHealth in Columbus, and her colleagues conducted this study.

Researchers used data collected between January 2012 and December 2014 from the Truven MarketScan Commercial Claims Databases, which included administrative claims and eligibility records of 80 million commercially insured people from the United States. Demographic information included age at index date, sex, type of health plan, and region of residence. The mean patient age was 43.2 for patients who initiated glatiramer acetate and 48.6 for patients who initiated teriflunomide. Between 76.9% and 84.1% of patients were female.

Jacqueline Nicholas, MD, MPH

Patients with MS who initiated a disease-modifying therapy in 2013 were analyzed. The index date was defined as the first claim for the disease-modifying therapy. Only patients with no disease-modifying therapy exposure in the year before the index date were included in this study. Researchers evaluated baseline clinical characteristics based on claims dated within one year before the index date and included chronic disease burden (measured using Charlson Comorbidity Index and MS-related symptoms).

Health care resource utilization was defined as the proportion of patients who were hospitalized or who had visited the emergency room during one year before and one year after the index date. Total health care costs were estimated for one year before and one year after the index date. Costs of prescriptions were not included, and costs were adjusted to the 2014 values based on the Consumer Price Index Medical Component.

There was a significant increase in health care costs in the post-index period for all disease-modifying therapies. Patients receiving dimethyl fumarate had a lower increase in their health care costs, compared with patients receiving interferon β, glatiramer acetate, or fingolimod. Following the initiation of disease-modifying therapy, medical costs decreased significantly among patients receiving dimethyl fumarate or interferon β.

Medical cost reductions (excluding prescription medicine costs) were highly dependent on a decreased use of outpatient services and hospital stays, which suggests that the increased costs of disease-modifying therapies are partially offset by reduced health resource utilization and costs.

One limitation of this study was that it focused on health resource utilization and costs only one year before and one year after initiation of disease-modifying therapy. Researchers recommend that future studies assess outcomes over a longer period of time. In addition, the claims data were not collected specifically for clinical research and did not provide the clinical information needed to assess disease severity.

This study was supported by Biogen.

—Erica Robinson

NATIONAL HARBOR, MD—Total health care costs increase following initiation of a disease-modifying therapy for multiple sclerosis (MS), but a subsequent overall decrease in health care resource utilization may partially offset the increased costs, according to data presented at the 2016 CMSC Annual Meeting. Upon initiation of disease-modifying therapy, total health care costs increase by $38,561 for patients receiving dimethyl fumarate and by $53,626 for patients receiving fingolimod.

There are limited real-world data on comparative health care resource utilization and costs associated with disease-modifying therapy use in routine clinical practice. Researchers decided to further investigate the effect of the initiation of disease-modifying therapy (ie, dimethyl fumarate, interferon β, glatiramer acetate, teriflunomide, or fingolimod) on health care resource utilization. Jacqueline Nicholas, MD, MPH, a neuroimmunologist at OhioHealth in Columbus, and her colleagues conducted this study.

Researchers used data collected between January 2012 and December 2014 from the Truven MarketScan Commercial Claims Databases, which included administrative claims and eligibility records of 80 million commercially insured people from the United States. Demographic information included age at index date, sex, type of health plan, and region of residence. The mean patient age was 43.2 for patients who initiated glatiramer acetate and 48.6 for patients who initiated teriflunomide. Between 76.9% and 84.1% of patients were female.

Jacqueline Nicholas, MD, MPH

Patients with MS who initiated a disease-modifying therapy in 2013 were analyzed. The index date was defined as the first claim for the disease-modifying therapy. Only patients with no disease-modifying therapy exposure in the year before the index date were included in this study. Researchers evaluated baseline clinical characteristics based on claims dated within one year before the index date and included chronic disease burden (measured using Charlson Comorbidity Index and MS-related symptoms).

Health care resource utilization was defined as the proportion of patients who were hospitalized or who had visited the emergency room during one year before and one year after the index date. Total health care costs were estimated for one year before and one year after the index date. Costs of prescriptions were not included, and costs were adjusted to the 2014 values based on the Consumer Price Index Medical Component.

There was a significant increase in health care costs in the post-index period for all disease-modifying therapies. Patients receiving dimethyl fumarate had a lower increase in their health care costs, compared with patients receiving interferon β, glatiramer acetate, or fingolimod. Following the initiation of disease-modifying therapy, medical costs decreased significantly among patients receiving dimethyl fumarate or interferon β.

Medical cost reductions (excluding prescription medicine costs) were highly dependent on a decreased use of outpatient services and hospital stays, which suggests that the increased costs of disease-modifying therapies are partially offset by reduced health resource utilization and costs.

One limitation of this study was that it focused on health resource utilization and costs only one year before and one year after initiation of disease-modifying therapy. Researchers recommend that future studies assess outcomes over a longer period of time. In addition, the claims data were not collected specifically for clinical research and did not provide the clinical information needed to assess disease severity.

This study was supported by Biogen.

—Erica Robinson

NATIONAL HARBOR, MD—Total health care costs increase following initiation of a disease-modifying therapy for multiple sclerosis (MS), but a subsequent overall decrease in health care resource utilization may partially offset the increased costs, according to data presented at the 2016 CMSC Annual Meeting. Upon initiation of disease-modifying therapy, total health care costs increase by $38,561 for patients receiving dimethyl fumarate and by $53,626 for patients receiving fingolimod.

There are limited real-world data on comparative health care resource utilization and costs associated with disease-modifying therapy use in routine clinical practice. Researchers decided to further investigate the effect of the initiation of disease-modifying therapy (ie, dimethyl fumarate, interferon β, glatiramer acetate, teriflunomide, or fingolimod) on health care resource utilization. Jacqueline Nicholas, MD, MPH, a neuroimmunologist at OhioHealth in Columbus, and her colleagues conducted this study.

Researchers used data collected between January 2012 and December 2014 from the Truven MarketScan Commercial Claims Databases, which included administrative claims and eligibility records of 80 million commercially insured people from the United States. Demographic information included age at index date, sex, type of health plan, and region of residence. The mean patient age was 43.2 for patients who initiated glatiramer acetate and 48.6 for patients who initiated teriflunomide. Between 76.9% and 84.1% of patients were female.

Jacqueline Nicholas, MD, MPH

Patients with MS who initiated a disease-modifying therapy in 2013 were analyzed. The index date was defined as the first claim for the disease-modifying therapy. Only patients with no disease-modifying therapy exposure in the year before the index date were included in this study. Researchers evaluated baseline clinical characteristics based on claims dated within one year before the index date and included chronic disease burden (measured using Charlson Comorbidity Index and MS-related symptoms).

Health care resource utilization was defined as the proportion of patients who were hospitalized or who had visited the emergency room during one year before and one year after the index date. Total health care costs were estimated for one year before and one year after the index date. Costs of prescriptions were not included, and costs were adjusted to the 2014 values based on the Consumer Price Index Medical Component.

There was a significant increase in health care costs in the post-index period for all disease-modifying therapies. Patients receiving dimethyl fumarate had a lower increase in their health care costs, compared with patients receiving interferon β, glatiramer acetate, or fingolimod. Following the initiation of disease-modifying therapy, medical costs decreased significantly among patients receiving dimethyl fumarate or interferon β.

Medical cost reductions (excluding prescription medicine costs) were highly dependent on a decreased use of outpatient services and hospital stays, which suggests that the increased costs of disease-modifying therapies are partially offset by reduced health resource utilization and costs.

One limitation of this study was that it focused on health resource utilization and costs only one year before and one year after initiation of disease-modifying therapy. Researchers recommend that future studies assess outcomes over a longer period of time. In addition, the claims data were not collected specifically for clinical research and did not provide the clinical information needed to assess disease severity.

This study was supported by Biogen.

—Erica Robinson

Higher hospital and surgeon volumes have been found to be correlated with improved outcomes after open repair of abdominal aortic aneurysm (AAA). However, the effect of both surgeon and hospital volumes on open and endovascular repair (EVAR) in the current era remains unclear, according to Dr. Sara L. Zettervall.

Dr. Zettervall of the Beth Israel Deaconess Medical Center will present a study that she and her colleagues performed on all Medicare beneficiaries who underwent elective AAA repair from 2001 to 2008.

They measured volume by repair type for the 1-year period before repair and assessed all AAA repairs (including elective, ruptured, contiguous, etc.). They used continuous volume and also divided volume into quintiles, which were constructed based on annual volumes across the entire study period for surgeons and hospitals, according to Dr. Zettervall.

A total of 122,495 patients underwent repair of an aortic aneurysm (open: 45,451 patients, EVAR: 77,044).

When examining surgeon and hospital volume together, EVAR perioperative mortality was not signficantly associated with surgeon volume, but was with hospital volume (OR, 1.5), according to Dr. Zettervall.

“Surgeon volume independently predicts mortality following open AAA repair,” said Dr. Zettervall. “In contrast, surgeon volume was not associated with mortality following EVAR, but hospital volume remained associated with patient survival,” she concluded.

Vess Paper
SESSION 1
8:00 – 11:30 a.m. Thursday
Maryland Ballroom A

Higher hospital and surgeon volumes have been found to be correlated with improved outcomes after open repair of abdominal aortic aneurysm (AAA). However, the effect of both surgeon and hospital volumes on open and endovascular repair (EVAR) in the current era remains unclear, according to Dr. Sara L. Zettervall.

Dr. Zettervall of the Beth Israel Deaconess Medical Center will present a study that she and her colleagues performed on all Medicare beneficiaries who underwent elective AAA repair from 2001 to 2008.

They measured volume by repair type for the 1-year period before repair and assessed all AAA repairs (including elective, ruptured, contiguous, etc.). They used continuous volume and also divided volume into quintiles, which were constructed based on annual volumes across the entire study period for surgeons and hospitals, according to Dr. Zettervall.

A total of 122,495 patients underwent repair of an aortic aneurysm (open: 45,451 patients, EVAR: 77,044).

When examining surgeon and hospital volume together, EVAR perioperative mortality was not signficantly associated with surgeon volume, but was with hospital volume (OR, 1.5), according to Dr. Zettervall.

“Surgeon volume independently predicts mortality following open AAA repair,” said Dr. Zettervall. “In contrast, surgeon volume was not associated with mortality following EVAR, but hospital volume remained associated with patient survival,” she concluded.

Vess Paper
SESSION 1
8:00 – 11:30 a.m. Thursday
Maryland Ballroom A

Higher hospital and surgeon volumes have been found to be correlated with improved outcomes after open repair of abdominal aortic aneurysm (AAA). However, the effect of both surgeon and hospital volumes on open and endovascular repair (EVAR) in the current era remains unclear, according to Dr. Sara L. Zettervall.

Dr. Zettervall of the Beth Israel Deaconess Medical Center will present a study that she and her colleagues performed on all Medicare beneficiaries who underwent elective AAA repair from 2001 to 2008.

They measured volume by repair type for the 1-year period before repair and assessed all AAA repairs (including elective, ruptured, contiguous, etc.). They used continuous volume and also divided volume into quintiles, which were constructed based on annual volumes across the entire study period for surgeons and hospitals, according to Dr. Zettervall.

A total of 122,495 patients underwent repair of an aortic aneurysm (open: 45,451 patients, EVAR: 77,044).

When examining surgeon and hospital volume together, EVAR perioperative mortality was not signficantly associated with surgeon volume, but was with hospital volume (OR, 1.5), according to Dr. Zettervall.

“Surgeon volume independently predicts mortality following open AAA repair,” said Dr. Zettervall. “In contrast, surgeon volume was not associated with mortality following EVAR, but hospital volume remained associated with patient survival,” she concluded.

Vess Paper
SESSION 1
8:00 – 11:30 a.m. Thursday
Maryland Ballroom A

NATIONAL HARBOR, MD—After eight years of fingolimod treatment, disability improves or remains stable for a majority of patients with relapsing-remitting multiple sclerosis (MS), according to data presented at the 2016 CMSC Annual Meeting.

The two-year phase III FREEDOMS and FREEDOMS II trial data revealed that fingolimod reduced confirmed disability progression in patients with MS, but evaluating disability over a longer time span may help to determine the full impact of treatment. Shannon Ritter, MD, an employee of Novartis Pharmaceuticals, and her colleagues examined trends in changes in Expanded Disability Status Scale (EDSS) scores over a maximum of eight years. Their objective was to investigate patients’ evolving disability patterns and the impact of fingolimod treatment on long-term disability.

The investigators conducted post hoc analyses that included data collected for as long as 96 months from baseline from patients randomized to fingolimod 0.5 mg or placebo in both two- year FREEDOMS trials. In addition, patients who switched or continued 0.5 mg fingolimod in the extension trials, and those who continuously received 0.5 mg fingolimod in the LONGTERMS trial, were also included in the analysis.

Disability progression was considered minimal if there was an increase or decrease of 0.5 points from a baseline EDSS score of 5.5 or lower, or if there was no change in a baseline score greater than 5.5. Disability was considered to have improved if the baseline EDSS score decreased by 1.0 or more points, either confirmed at six months only, or confirmed at six months and sustained until month 24, 48, or 96. Worsening was defined as an increase of 1.0 point or more from the baseline EDSS score, either confirmed at six months only or confirmed at six months and sustained until month 24, 48, and 96. Stable/improving was defined as the minimal and improving categories combined, and fluctuating was identified as changes in the EDSS score that were different from those defined in other categories.

Results showed that significant improvements were more likely to be noted after longer periods of continuous fingolimod treatment. Disability fluctuated or changed minimally at 24 months, and the proportion of patients in these categories decreased by almost 50% at 96 months. Researchers noted that 22.6% of patients in the continuous fingolimod group were improving, 22.6% were worsening, and 54.7% of patients had minimal change or were fluctuating at 96 months. However, 20% of patients in the switch group were improving, 28% were worsening, and 52% had changed minimally or were fluctuating at 96 months. Overall, the proportion of patients improving or worsening was larger at 96 months than at 24 months.

Researchers also investigated the impact of delaying fingolimod treatment on long-term disability and concluded that patients with worsening disability over 96 months benefited from early fingolimod treatment. Fewer patients in the continuous fingolimod group had worsening disability, compared with the switch group, at 24 months. By 96 months, the continuous fingolimod group maintained proportionally fewer patients with worsening disability, compared with the switch group. The data indicate that the majority of patients receiving continuous fingolimod treatment were either stable or improving at 96 months. Proportionally more patients had improving disability at 96 months, compared to 24 months. These results support the practice of longer follow-up periods to properly detect the impact of treatment.

This study was supported by Oxford PharmaGenesis in Oxford UK, and funded by Novartis Pharmaceuticals.

—Erica Robinson

NATIONAL HARBOR, MD—After eight years of fingolimod treatment, disability improves or remains stable for a majority of patients with relapsing-remitting multiple sclerosis (MS), according to data presented at the 2016 CMSC Annual Meeting.

The two-year phase III FREEDOMS and FREEDOMS II trial data revealed that fingolimod reduced confirmed disability progression in patients with MS, but evaluating disability over a longer time span may help to determine the full impact of treatment. Shannon Ritter, MD, an employee of Novartis Pharmaceuticals, and her colleagues examined trends in changes in Expanded Disability Status Scale (EDSS) scores over a maximum of eight years. Their objective was to investigate patients’ evolving disability patterns and the impact of fingolimod treatment on long-term disability.

The investigators conducted post hoc analyses that included data collected for as long as 96 months from baseline from patients randomized to fingolimod 0.5 mg or placebo in both two- year FREEDOMS trials. In addition, patients who switched or continued 0.5 mg fingolimod in the extension trials, and those who continuously received 0.5 mg fingolimod in the LONGTERMS trial, were also included in the analysis.

Disability progression was considered minimal if there was an increase or decrease of 0.5 points from a baseline EDSS score of 5.5 or lower, or if there was no change in a baseline score greater than 5.5. Disability was considered to have improved if the baseline EDSS score decreased by 1.0 or more points, either confirmed at six months only, or confirmed at six months and sustained until month 24, 48, or 96. Worsening was defined as an increase of 1.0 point or more from the baseline EDSS score, either confirmed at six months only or confirmed at six months and sustained until month 24, 48, and 96. Stable/improving was defined as the minimal and improving categories combined, and fluctuating was identified as changes in the EDSS score that were different from those defined in other categories.

Results showed that significant improvements were more likely to be noted after longer periods of continuous fingolimod treatment. Disability fluctuated or changed minimally at 24 months, and the proportion of patients in these categories decreased by almost 50% at 96 months. Researchers noted that 22.6% of patients in the continuous fingolimod group were improving, 22.6% were worsening, and 54.7% of patients had minimal change or were fluctuating at 96 months. However, 20% of patients in the switch group were improving, 28% were worsening, and 52% had changed minimally or were fluctuating at 96 months. Overall, the proportion of patients improving or worsening was larger at 96 months than at 24 months.

Researchers also investigated the impact of delaying fingolimod treatment on long-term disability and concluded that patients with worsening disability over 96 months benefited from early fingolimod treatment. Fewer patients in the continuous fingolimod group had worsening disability, compared with the switch group, at 24 months. By 96 months, the continuous fingolimod group maintained proportionally fewer patients with worsening disability, compared with the switch group. The data indicate that the majority of patients receiving continuous fingolimod treatment were either stable or improving at 96 months. Proportionally more patients had improving disability at 96 months, compared to 24 months. These results support the practice of longer follow-up periods to properly detect the impact of treatment.

This study was supported by Oxford PharmaGenesis in Oxford UK, and funded by Novartis Pharmaceuticals.

—Erica Robinson

NATIONAL HARBOR, MD—After eight years of fingolimod treatment, disability improves or remains stable for a majority of patients with relapsing-remitting multiple sclerosis (MS), according to data presented at the 2016 CMSC Annual Meeting.

The two-year phase III FREEDOMS and FREEDOMS II trial data revealed that fingolimod reduced confirmed disability progression in patients with MS, but evaluating disability over a longer time span may help to determine the full impact of treatment. Shannon Ritter, MD, an employee of Novartis Pharmaceuticals, and her colleagues examined trends in changes in Expanded Disability Status Scale (EDSS) scores over a maximum of eight years. Their objective was to investigate patients’ evolving disability patterns and the impact of fingolimod treatment on long-term disability.

The investigators conducted post hoc analyses that included data collected for as long as 96 months from baseline from patients randomized to fingolimod 0.5 mg or placebo in both two- year FREEDOMS trials. In addition, patients who switched or continued 0.5 mg fingolimod in the extension trials, and those who continuously received 0.5 mg fingolimod in the LONGTERMS trial, were also included in the analysis.

Disability progression was considered minimal if there was an increase or decrease of 0.5 points from a baseline EDSS score of 5.5 or lower, or if there was no change in a baseline score greater than 5.5. Disability was considered to have improved if the baseline EDSS score decreased by 1.0 or more points, either confirmed at six months only, or confirmed at six months and sustained until month 24, 48, or 96. Worsening was defined as an increase of 1.0 point or more from the baseline EDSS score, either confirmed at six months only or confirmed at six months and sustained until month 24, 48, and 96. Stable/improving was defined as the minimal and improving categories combined, and fluctuating was identified as changes in the EDSS score that were different from those defined in other categories.

Results showed that significant improvements were more likely to be noted after longer periods of continuous fingolimod treatment. Disability fluctuated or changed minimally at 24 months, and the proportion of patients in these categories decreased by almost 50% at 96 months. Researchers noted that 22.6% of patients in the continuous fingolimod group were improving, 22.6% were worsening, and 54.7% of patients had minimal change or were fluctuating at 96 months. However, 20% of patients in the switch group were improving, 28% were worsening, and 52% had changed minimally or were fluctuating at 96 months. Overall, the proportion of patients improving or worsening was larger at 96 months than at 24 months.

Researchers also investigated the impact of delaying fingolimod treatment on long-term disability and concluded that patients with worsening disability over 96 months benefited from early fingolimod treatment. Fewer patients in the continuous fingolimod group had worsening disability, compared with the switch group, at 24 months. By 96 months, the continuous fingolimod group maintained proportionally fewer patients with worsening disability, compared with the switch group. The data indicate that the majority of patients receiving continuous fingolimod treatment were either stable or improving at 96 months. Proportionally more patients had improving disability at 96 months, compared to 24 months. These results support the practice of longer follow-up periods to properly detect the impact of treatment.

This study was supported by Oxford PharmaGenesis in Oxford UK, and funded by Novartis Pharmaceuticals.

—Erica Robinson

CHICAGO – The novel antibody IMAB362 extended survival of patients with advanced gastric cancer when added to chemotherapy, according to a phase II trial presented at the annual meeting of the Society of Clinical Oncology.

IMAB362 is a first-in-class monoclonal antibody targeting claudin18.2, a protein component of cellular tight junctions abundant in gastric tumors, as well as tumors of the pancreas, lung, esophagus, and ovaries.

IMAB362 significantly extended median overall survival (OS) when added to standard chemotherapy (13.2 vs. 8.4 months, hazard ratio [HR] = 0.51, P = .0001). Patients with the highest levels of claudin18.2 had an even longer median overall survival (16.7 vs. 9.0 months, HR = 0.45, P less than .0005).

The FAST (Phase II First-Line Therapy in Patients With Advanced CLDN18.2+ Gastric and Gastroesophageal Junction Adenocarcinoma) trial included patients who had no prior chemotherapy for locally advanced or metastatic disease. Tumors had to have 2+/3+ CLDN18.2 expression in 40% or more of tumor cells, and patients had an Eastern Cooperative Oncology Group performance status of 0-1.

Patients with tumors that expressed higher levels of claudin18,2, the target antigen, did better than the overall cohort in terms of progression-free survival (PFS), the primary endpoint.

“The FAST trial clearly met its primary endpoint, and there is a significant improvement in PFS and OS in the entire cohort and also in the higher expressers,” lead author Dr. Salah-Eddin Al-Batran, medical director of the Institute of Clinical Cancer Research, Nordwest Hospital in Frankfurst am Main, Germany, said in a news conference at the meeting.

The IMAB362 monoclonal antibody is highly specific for CLDN18.2 and works through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. In combination with chemotherapy, by binding to tumor debris, it is an immunomodulator of the tumor microenvironment.

About 50% of gastric tumors express CLDN18.2. After screening, the investigators randomized 246 patients to three treatment arms: epirubicin/oxaliplatin/capecitabine (EOX), n = 84; EOX + IMAB362 at a loading dose of 800 mg/m², then 600 mg/m² on day 1 every 3 weeks, n = 77; or a higher dose of IMAB362 with EOX, n = 85. Dr. Al-Batran reported results of the first two arms and will present results for the third arm at a later time.

Median progression-free survival was 4.8 months with EOX and 7.9 months with EOX plus IMAB362 (HR = .47; P = .0001).

If 70% or more of the tumor cells expressed CLDN18.2, IMAB362 improved the median PFS from 5.6 months for EOX alone to 7.2 months (HR = 0.36, P less than .0005), and OS improved from 9 months to 16.7 months (HR = 0.45, P less than .0005).

Response rates were also better with the addition of IMAB362. The objective response rate by RECIST criteria was 39.0% with EOX + IMAB362 vs. 25.0% with EOX alone. Most of the responses were partial (28.6% vs. 21.4%, respectively) or stable disease (44.2% vs. 51.2%, respectively). There were only 10.4% complete responses with IMAB362 and 3.6% with EOX alone. About 12% of the patients in each arm were not evaluable, or the data were missing.

Both treatments were well tolerated, with most adverse effects being grade 1/2. However, there was more grade 3/4 neutropenia with the combination (32.5% vs. 21.4% for EOX alone) as well as grade 3/4 vomiting (10.4% vs. 3.6%, respectively). Grade 1/2 vomiting was common in both arms, with about one-third of patients receiving EOX alone and just over half of patients on EOX + IMAB362 being affected.

Susan London

Dr. Al-Batran said that there may have been more vomiting with IMAB362 because tight junction proteins, including claudin, are present in the gastric mucosa. Diarrhea was largely grade 1/2, affected about one-third of patients receiving EOX alone, and was only about half as common among patients receiving the combination.

Dr. Al-Batran said this trial “provides a strong rationale for a confirmatory phase III trial.”

Press conference moderator Dr. Smitha Krishnamurthi said the study is important because it documents the activity of a first-in-class antibody in patients with advanced gastric and gastroesophageal junction cancers. Since CLDN18.2 is expressed in about 50% of these cancers, “this treatment could apply to many patients,” she said.

The study was initiated and sponsored by Ganymed Pharmaceuticals. Dr. Al-Batran has had a consulting or advisory role with Merck, Roche, Celgene, and Lilly; has been on the speakers bureau of Lilly, Roche, Celgene, and Nordic Bioscience; and has received research funding from Celgene, Roche Pharma, Lilly, Novartis, Vfor Pharma, Medac, and Hospira.

On Twitter @OncologyPractic

CHICAGO – The novel antibody IMAB362 extended survival of patients with advanced gastric cancer when added to chemotherapy, according to a phase II trial presented at the annual meeting of the Society of Clinical Oncology.

IMAB362 is a first-in-class monoclonal antibody targeting claudin18.2, a protein component of cellular tight junctions abundant in gastric tumors, as well as tumors of the pancreas, lung, esophagus, and ovaries.

IMAB362 significantly extended median overall survival (OS) when added to standard chemotherapy (13.2 vs. 8.4 months, hazard ratio [HR] = 0.51, P = .0001). Patients with the highest levels of claudin18.2 had an even longer median overall survival (16.7 vs. 9.0 months, HR = 0.45, P less than .0005).

The FAST (Phase II First-Line Therapy in Patients With Advanced CLDN18.2+ Gastric and Gastroesophageal Junction Adenocarcinoma) trial included patients who had no prior chemotherapy for locally advanced or metastatic disease. Tumors had to have 2+/3+ CLDN18.2 expression in 40% or more of tumor cells, and patients had an Eastern Cooperative Oncology Group performance status of 0-1.

Patients with tumors that expressed higher levels of claudin18,2, the target antigen, did better than the overall cohort in terms of progression-free survival (PFS), the primary endpoint.

“The FAST trial clearly met its primary endpoint, and there is a significant improvement in PFS and OS in the entire cohort and also in the higher expressers,” lead author Dr. Salah-Eddin Al-Batran, medical director of the Institute of Clinical Cancer Research, Nordwest Hospital in Frankfurst am Main, Germany, said in a news conference at the meeting.

The IMAB362 monoclonal antibody is highly specific for CLDN18.2 and works through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. In combination with chemotherapy, by binding to tumor debris, it is an immunomodulator of the tumor microenvironment.

About 50% of gastric tumors express CLDN18.2. After screening, the investigators randomized 246 patients to three treatment arms: epirubicin/oxaliplatin/capecitabine (EOX), n = 84; EOX + IMAB362 at a loading dose of 800 mg/m², then 600 mg/m² on day 1 every 3 weeks, n = 77; or a higher dose of IMAB362 with EOX, n = 85. Dr. Al-Batran reported results of the first two arms and will present results for the third arm at a later time.

Median progression-free survival was 4.8 months with EOX and 7.9 months with EOX plus IMAB362 (HR = .47; P = .0001).

If 70% or more of the tumor cells expressed CLDN18.2, IMAB362 improved the median PFS from 5.6 months for EOX alone to 7.2 months (HR = 0.36, P less than .0005), and OS improved from 9 months to 16.7 months (HR = 0.45, P less than .0005).

Response rates were also better with the addition of IMAB362. The objective response rate by RECIST criteria was 39.0% with EOX + IMAB362 vs. 25.0% with EOX alone. Most of the responses were partial (28.6% vs. 21.4%, respectively) or stable disease (44.2% vs. 51.2%, respectively). There were only 10.4% complete responses with IMAB362 and 3.6% with EOX alone. About 12% of the patients in each arm were not evaluable, or the data were missing.

Both treatments were well tolerated, with most adverse effects being grade 1/2. However, there was more grade 3/4 neutropenia with the combination (32.5% vs. 21.4% for EOX alone) as well as grade 3/4 vomiting (10.4% vs. 3.6%, respectively). Grade 1/2 vomiting was common in both arms, with about one-third of patients receiving EOX alone and just over half of patients on EOX + IMAB362 being affected.

Susan London

Dr. Al-Batran said that there may have been more vomiting with IMAB362 because tight junction proteins, including claudin, are present in the gastric mucosa. Diarrhea was largely grade 1/2, affected about one-third of patients receiving EOX alone, and was only about half as common among patients receiving the combination.

Dr. Al-Batran said this trial “provides a strong rationale for a confirmatory phase III trial.”

Press conference moderator Dr. Smitha Krishnamurthi said the study is important because it documents the activity of a first-in-class antibody in patients with advanced gastric and gastroesophageal junction cancers. Since CLDN18.2 is expressed in about 50% of these cancers, “this treatment could apply to many patients,” she said.

The study was initiated and sponsored by Ganymed Pharmaceuticals. Dr. Al-Batran has had a consulting or advisory role with Merck, Roche, Celgene, and Lilly; has been on the speakers bureau of Lilly, Roche, Celgene, and Nordic Bioscience; and has received research funding from Celgene, Roche Pharma, Lilly, Novartis, Vfor Pharma, Medac, and Hospira.

On Twitter @OncologyPractic

CHICAGO – The novel antibody IMAB362 extended survival of patients with advanced gastric cancer when added to chemotherapy, according to a phase II trial presented at the annual meeting of the Society of Clinical Oncology.

IMAB362 is a first-in-class monoclonal antibody targeting claudin18.2, a protein component of cellular tight junctions abundant in gastric tumors, as well as tumors of the pancreas, lung, esophagus, and ovaries.

IMAB362 significantly extended median overall survival (OS) when added to standard chemotherapy (13.2 vs. 8.4 months, hazard ratio [HR] = 0.51, P = .0001). Patients with the highest levels of claudin18.2 had an even longer median overall survival (16.7 vs. 9.0 months, HR = 0.45, P less than .0005).

The FAST (Phase II First-Line Therapy in Patients With Advanced CLDN18.2+ Gastric and Gastroesophageal Junction Adenocarcinoma) trial included patients who had no prior chemotherapy for locally advanced or metastatic disease. Tumors had to have 2+/3+ CLDN18.2 expression in 40% or more of tumor cells, and patients had an Eastern Cooperative Oncology Group performance status of 0-1.

Patients with tumors that expressed higher levels of claudin18,2, the target antigen, did better than the overall cohort in terms of progression-free survival (PFS), the primary endpoint.

“The FAST trial clearly met its primary endpoint, and there is a significant improvement in PFS and OS in the entire cohort and also in the higher expressers,” lead author Dr. Salah-Eddin Al-Batran, medical director of the Institute of Clinical Cancer Research, Nordwest Hospital in Frankfurst am Main, Germany, said in a news conference at the meeting.

The IMAB362 monoclonal antibody is highly specific for CLDN18.2 and works through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. In combination with chemotherapy, by binding to tumor debris, it is an immunomodulator of the tumor microenvironment.

About 50% of gastric tumors express CLDN18.2. After screening, the investigators randomized 246 patients to three treatment arms: epirubicin/oxaliplatin/capecitabine (EOX), n = 84; EOX + IMAB362 at a loading dose of 800 mg/m², then 600 mg/m² on day 1 every 3 weeks, n = 77; or a higher dose of IMAB362 with EOX, n = 85. Dr. Al-Batran reported results of the first two arms and will present results for the third arm at a later time.

Median progression-free survival was 4.8 months with EOX and 7.9 months with EOX plus IMAB362 (HR = .47; P = .0001).

If 70% or more of the tumor cells expressed CLDN18.2, IMAB362 improved the median PFS from 5.6 months for EOX alone to 7.2 months (HR = 0.36, P less than .0005), and OS improved from 9 months to 16.7 months (HR = 0.45, P less than .0005).

Response rates were also better with the addition of IMAB362. The objective response rate by RECIST criteria was 39.0% with EOX + IMAB362 vs. 25.0% with EOX alone. Most of the responses were partial (28.6% vs. 21.4%, respectively) or stable disease (44.2% vs. 51.2%, respectively). There were only 10.4% complete responses with IMAB362 and 3.6% with EOX alone. About 12% of the patients in each arm were not evaluable, or the data were missing.

Both treatments were well tolerated, with most adverse effects being grade 1/2. However, there was more grade 3/4 neutropenia with the combination (32.5% vs. 21.4% for EOX alone) as well as grade 3/4 vomiting (10.4% vs. 3.6%, respectively). Grade 1/2 vomiting was common in both arms, with about one-third of patients receiving EOX alone and just over half of patients on EOX + IMAB362 being affected.

Susan London

Dr. Al-Batran said that there may have been more vomiting with IMAB362 because tight junction proteins, including claudin, are present in the gastric mucosa. Diarrhea was largely grade 1/2, affected about one-third of patients receiving EOX alone, and was only about half as common among patients receiving the combination.

Dr. Al-Batran said this trial “provides a strong rationale for a confirmatory phase III trial.”

Press conference moderator Dr. Smitha Krishnamurthi said the study is important because it documents the activity of a first-in-class antibody in patients with advanced gastric and gastroesophageal junction cancers. Since CLDN18.2 is expressed in about 50% of these cancers, “this treatment could apply to many patients,” she said.

The study was initiated and sponsored by Ganymed Pharmaceuticals. Dr. Al-Batran has had a consulting or advisory role with Merck, Roche, Celgene, and Lilly; has been on the speakers bureau of Lilly, Roche, Celgene, and Nordic Bioscience; and has received research funding from Celgene, Roche Pharma, Lilly, Novartis, Vfor Pharma, Medac, and Hospira.

On Twitter @OncologyPractic

NATIONAL HARBOR, MD—Risk of new or additional flu-like symptoms in patients with multiple sclerosis (MS) transitioning from nonpegylated interferon beta-1a to pegylated interferon beta-1a is low, according to a report at the 2016 CMSC Annual Meeting. Scheduled naproxen therapy may be a beneficial prophylactic strategy, according to researchers. “Ninety percent of patients did not experience new or worsening flu-like symptoms,” said Robert T. Naismith, MD, Associate Professor, Washington University School of Medicine, St. Louis, Missouri, and colleagues.

Robert T. Naismith, MD

Dr. Naismith and coinvestigators conducted the ALLOW study, a one-year, phase IIIb open-label, randomized trial to characterize flu-like symptoms in patients with relapsing MS who transitioned from nonpegylated interferon beta-1a to pegylated interferon beta-1a. The study included patients age 18 to 65 with relapsing MS who had been treated with a stable dose of nonpegylated interferon for four months or more prior to screening. Their drug regimen was continued throughout a four-week run-in period for evaluation of flu-like symptoms including influenza-like illness, myalgia, pyrexia, or asthenia on that regimen. All patients were then switched to pegylated interferon beta-1a titrated to 125 μg every two weeks. Patients were randomized one-to-one to continue their current flu-like symptom management or to commence a regimen of naproxen 500 mg twice daily, starting 24 hours before each dose of pegylated interferon beta-1a and continuing for 48 hours after, for the first eight weeks of treatment.

The primary end point was the proportion of patients experiencing new or worsening flu-like symptoms, which was defined as a 2 or more point increase in flu-like symptom score. Secondary end points were flu-like symptom severity over 48 weeks and impact of naproxen, the onset and duration of flu-like symptoms following pegylated interferon beta-1a injection, the incidence of adverse events, and walking as measured by the Patient Determined Disease Steps (PDDS), a self-assessment walking scale that ranges from normal (0) to bedridden (8).

Of 201 patients who were randomized, 81.6% within each arm completed the study. Baseline characteristics were balanced between the two arms. A majority (89.6%) of patients did not experience new or worsening flu-like symptoms during the first eight weeks of following treatment switch. Flu-like symptom severity remained low across all study populations through week 48, with a majority of the symptoms being mild to moderate. Naproxen did not reduce flu-like symptom severity compared with current flu-like symptom management regimen. Following injection, overall flu-like symptom onset occurred between a mean of 12.0 and 12.8 hours and lasted for a mean duration of 13.8 to 17.0 hours. The most common adverse events were injection-site erythema, injection-site reaction, and influenza-like illness. No significant increase in walking disability was reported by patients who completed the study.

This study was sponsored by Biogen.

—Glenn S. Williams

NATIONAL HARBOR, MD—Risk of new or additional flu-like symptoms in patients with multiple sclerosis (MS) transitioning from nonpegylated interferon beta-1a to pegylated interferon beta-1a is low, according to a report at the 2016 CMSC Annual Meeting. Scheduled naproxen therapy may be a beneficial prophylactic strategy, according to researchers. “Ninety percent of patients did not experience new or worsening flu-like symptoms,” said Robert T. Naismith, MD, Associate Professor, Washington University School of Medicine, St. Louis, Missouri, and colleagues.

Robert T. Naismith, MD

Dr. Naismith and coinvestigators conducted the ALLOW study, a one-year, phase IIIb open-label, randomized trial to characterize flu-like symptoms in patients with relapsing MS who transitioned from nonpegylated interferon beta-1a to pegylated interferon beta-1a. The study included patients age 18 to 65 with relapsing MS who had been treated with a stable dose of nonpegylated interferon for four months or more prior to screening. Their drug regimen was continued throughout a four-week run-in period for evaluation of flu-like symptoms including influenza-like illness, myalgia, pyrexia, or asthenia on that regimen. All patients were then switched to pegylated interferon beta-1a titrated to 125 μg every two weeks. Patients were randomized one-to-one to continue their current flu-like symptom management or to commence a regimen of naproxen 500 mg twice daily, starting 24 hours before each dose of pegylated interferon beta-1a and continuing for 48 hours after, for the first eight weeks of treatment.

The primary end point was the proportion of patients experiencing new or worsening flu-like symptoms, which was defined as a 2 or more point increase in flu-like symptom score. Secondary end points were flu-like symptom severity over 48 weeks and impact of naproxen, the onset and duration of flu-like symptoms following pegylated interferon beta-1a injection, the incidence of adverse events, and walking as measured by the Patient Determined Disease Steps (PDDS), a self-assessment walking scale that ranges from normal (0) to bedridden (8).

Of 201 patients who were randomized, 81.6% within each arm completed the study. Baseline characteristics were balanced between the two arms. A majority (89.6%) of patients did not experience new or worsening flu-like symptoms during the first eight weeks of following treatment switch. Flu-like symptom severity remained low across all study populations through week 48, with a majority of the symptoms being mild to moderate. Naproxen did not reduce flu-like symptom severity compared with current flu-like symptom management regimen. Following injection, overall flu-like symptom onset occurred between a mean of 12.0 and 12.8 hours and lasted for a mean duration of 13.8 to 17.0 hours. The most common adverse events were injection-site erythema, injection-site reaction, and influenza-like illness. No significant increase in walking disability was reported by patients who completed the study.

This study was sponsored by Biogen.

—Glenn S. Williams

NATIONAL HARBOR, MD—Risk of new or additional flu-like symptoms in patients with multiple sclerosis (MS) transitioning from nonpegylated interferon beta-1a to pegylated interferon beta-1a is low, according to a report at the 2016 CMSC Annual Meeting. Scheduled naproxen therapy may be a beneficial prophylactic strategy, according to researchers. “Ninety percent of patients did not experience new or worsening flu-like symptoms,” said Robert T. Naismith, MD, Associate Professor, Washington University School of Medicine, St. Louis, Missouri, and colleagues.

Robert T. Naismith, MD

Dr. Naismith and coinvestigators conducted the ALLOW study, a one-year, phase IIIb open-label, randomized trial to characterize flu-like symptoms in patients with relapsing MS who transitioned from nonpegylated interferon beta-1a to pegylated interferon beta-1a. The study included patients age 18 to 65 with relapsing MS who had been treated with a stable dose of nonpegylated interferon for four months or more prior to screening. Their drug regimen was continued throughout a four-week run-in period for evaluation of flu-like symptoms including influenza-like illness, myalgia, pyrexia, or asthenia on that regimen. All patients were then switched to pegylated interferon beta-1a titrated to 125 μg every two weeks. Patients were randomized one-to-one to continue their current flu-like symptom management or to commence a regimen of naproxen 500 mg twice daily, starting 24 hours before each dose of pegylated interferon beta-1a and continuing for 48 hours after, for the first eight weeks of treatment.

The primary end point was the proportion of patients experiencing new or worsening flu-like symptoms, which was defined as a 2 or more point increase in flu-like symptom score. Secondary end points were flu-like symptom severity over 48 weeks and impact of naproxen, the onset and duration of flu-like symptoms following pegylated interferon beta-1a injection, the incidence of adverse events, and walking as measured by the Patient Determined Disease Steps (PDDS), a self-assessment walking scale that ranges from normal (0) to bedridden (8).

Of 201 patients who were randomized, 81.6% within each arm completed the study. Baseline characteristics were balanced between the two arms. A majority (89.6%) of patients did not experience new or worsening flu-like symptoms during the first eight weeks of following treatment switch. Flu-like symptom severity remained low across all study populations through week 48, with a majority of the symptoms being mild to moderate. Naproxen did not reduce flu-like symptom severity compared with current flu-like symptom management regimen. Following injection, overall flu-like symptom onset occurred between a mean of 12.0 and 12.8 hours and lasted for a mean duration of 13.8 to 17.0 hours. The most common adverse events were injection-site erythema, injection-site reaction, and influenza-like illness. No significant increase in walking disability was reported by patients who completed the study.

This study was sponsored by Biogen.

—Glenn S. Williams

We live in a time when young, otherwise healthy, active-duty individuals are undergoing traumatic amputations at an exceedingly high rate due to ongoing military engagements. According to US military casualty statistics through September 1, 2014, Operation Iraqi Freedom, Operation Enduring Freedom, and Operation New Dawn veterans have undergone a total of 1573 amputations.¹ Walter Reed National Military Medical Center (WRNMMC) is one of several military facilities that has managed the care of these unique patients returning from the many ongoing conflicts around the globe. Multidisciplinary teams composed of surgeons, anesthesiologists, physical therapists, prosthetists, and others have joined forces to provide extraordinary emergency and recovery care for these patients. Even in the best hands, however, these traumatic amputee patients often experience long-term and lifelong sequelae of their injuries. As dermatologists at this facility (S.P. was at WRNMMC for 3 years before transferring to Madigan Army Medical Center), we are often asked to assist in the management of a subset of these sequelae: residual limb dermatoses. Residual limb dermatoses such as recurrent bacterial and fungal infections, cysts, abrasions, blistering, irritant and allergic dermatitis, pressure ulcers, acroangiodermatitis, stump edema, and many others have a high prevalence in our wounded warrior population and impact both amputee quality of life and utilization of medical resources. As many as 73% of amputees will experience a variety of residual limb dermatoses at some point in their life, with the highest prevalence in younger, more active patients.^2,3 We have observed that many, if not most, of these cutaneous problems can be attributed to or are exacerbated by hyperhidrosis of the residual limb. Hyperhidrosis in this population of patients can be related to excessive sweat production, but more commonly, it is attributed to the lack of evaporation of normal perspiration.

Excess Sweat and the Prosthesis

To understand hyperhidrosis in amputee patients, it is important to understand the anatomy of the prosthesis. There are a variety of materials that are used to create prosthetic limbs. The most commonly used materials are a combination of plastic and carbon graphite/carbon fiber. The modern prosthetic limb uses a suspension system that attaches the prosthetic limb to the residual limb by creating a vacuum. There are several mechanisms to create this vacuum; however, they all depend on a liner that fits snugly over the residual limb. This liner-limb interface is responsible for protection, mitigation of sheering forces, and comfort, and it is the anchor for a good fit in the prosthesis. Unfortunately, this liner is the primary factor contributing to residual limb dermatologic problems. The liner usually is made of silicone or polyurethane and is designed to be water and sweat resistant; any excess water that finds its way into the liner-prosthetic interface will affect the seal of the device and cause slippage of the prosthesis.⁴ This water-resistant barrier is what induces the hyperhidrotic environment over the residual limb that is covered. These patients sweat with exertion, and because of the water-resistant liner, there is no mechanism for sweat evaporation. This leads to a localized environment of hyperhidrosis, increasing patients’ susceptibility to chronic skin conditions. In addition to the dermatologic pathology of the residual limb, there are notable functional concerns caused by excessive sweating. Increased moisture due to sweating not only leads to pathologic dermatoses but also to impaired fit and loss of suction by leaking into the prosthetic-limb interface, which in turn can lead to decreased stamina in the prosthesis, falls, and in severe cases even prosthetic abandonment.⁵

Treating Hyperhidrosis

While working with wounded warriors in the dermatology, prosthetics, and wound care clinics at WRNMMC, it repeatedly became clear that our current treatment options for hyperhidrosis in this population were not routinely tolerated or efficacious. Although hyperhidrosis of the axillary or palmoplantar region is a commonly encountered problem with clear treatment algorithms and management strategies, hyperhidrosis in the setting of a residual limb following amputation is somewhat unique and without definitive permanent cure. In approaching this problem, our institution has implemented a variety of therapies to the residual limb that have been well described and effective in the treatment in the axillary region.

Topical antiperspirants (ie, aluminum chloride) are well-documented treatments of hyperhidrosis and work by the formation of a metal iron precipitate when binding with mucopolysaccharides. These complexes cause damage to epithelial cells lining the ostia of eccrine glands, forming a plug in the lumen of the eccrine duct.⁶ Unfortunately, irritant contact dermatitis has affected the majority of our residual limb patients who have used topical antiperspirants and has led to poor compliance. Glycopyrrolate, an antimuscarinic agent, often is used with varying degrees of success. It works as a competitive antagonist blocking the acetylcholine muscarinic receptors that are responsible for the innervation of eccrine sweat glands. Several of our residual limb patients have a history of global hyperhidrosis and have responded favorably to 1- to 2-mg doses of glycopyrrolate administered twice daily. The side-effect profile headlined by xerostomia, urinary retention, and constipation has, as it often does, limited the dosing. We have observed that with the use of glycopyrrolate, these patients admit to less overall sweating but experience only a mild decrease in the cutaneous problems they experience over the residual limbs, which is likely attributed to the prosthetic liner that induces hyperhidrosis by preventing sweat evaporation from the residual limb. Patients may not be sweating as much, but they are still sweating and that sweat is unable to evaporate from under the liner.

Botulinum toxin is a common treatment of axillary hyperhidrosis and its effects on residual limbs are the same.^5,7 Botulinum toxin types A, B, and E specifically cleave soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, which prevents neurosecretory vesicles from fusing with the interior surface of the plasma membrane of the nerve synapse, thereby blocking release of acetylcholine.⁸ In inhibiting acetylcholine release, the signal for eccrine secretion is blocked. This therapy has been effective in our residual limb patients who tolerate the treatment. It typically involves the injection of 300 to 500 U of botulinum toxin type A diluted with 0.9% saline at 2 to 5 U per 0.1 mL into the residual limb.⁵ As with the other treatments, there are side effects that complicate compliance. Most residual limb treatments require 150 injections, which can be uncomfortable for this patient cohort. The majority of these wounded warriors have abnormal anatomy because of the traumatic nature of their injuries (ie, improvised explosive device attacks, artillery injury), and they often experience hyperesthesia, phantom limb pain, and notable scarring. These injections can be extremely painful, which often limits their utility. In addition, the therapy only provides 3 to 6 months of symptom relief. Our compliance rate for returning patients has not been good and we suspect that it is likely due to the discomfort associated with the injections.

Other therapies such as laser hair removal and iontophoresis have been attempted but have not yielded great results or compliance. In addition to the limitations of these treatment methods, the residual limbs have presented their own unique set of challenges; complications have included varied anatomy of the residual limbs, scarring, sensitivities, and heterotopic ossification. Temporary remedies such as botulinum toxin injections also present logistical complications because they require repetitive procedural appointments that can be quite burdensome to attend when these patients move back home, often far away from our large military treatment facilities.

A New Therapy With Exciting Potential

With the recent advent of microwave thermal ablation technology, the potential for a different, possibly permanent treatment was discovered. Microwave thermal ablation of the eccrine coils has been proven safe and effective in the prolonged reduction of hyperhidrosis of the axillae and has presented as a potential therapy for our residual limb hyperhidrosis patient population. This technology produces heat that is targeted to a specific depth in the treated tissue while cooling the epidermis. There are various treatment levels that can be used to deliver graded intensities of heat. When the deep dermis is targeted, adnexal structures are denatured and destroyed, causing diminished or eliminated function. Eccrine sweat glands, apocrine glands, and even hair follicles are affected by the therapy. The manufacturer of the only microwave thermal ablation device on the market that is approved by the US Food and Drug Administration to treat axillary hyperhidrosis has suggested that these effects are long-term and possibly permanent.⁹ After several iterations with this technology, we have been able to successfully apply microwave thermal ablation of eccrine coils to 5 residual limbs and are excited about the promise that this technique possesses. A report of our index case will be published soon,¹⁰ and we are looking forward to launching our protocol treating traumatic lower extremity amputee patients that have hyperhidrosis with microwave therapy ablation technology here at WRNMMC.

Final Thoughts

Amputation residual limb dermatoses have a high prevalence and impact on amputee quality of life, particularly among young military members who strive to maintain a highly active lifestyle. Many of these dermatoses are directly related to hyperhidrosis of the residual limb that is covered by the prosthetic device and the liner that interfaces with the skin. Although many treatments for residual limb hyperhidrosis have been used with varying efficacy, none have offered a cost-effective or sustained response. Many of our wounded warriors in this amputee population have or will be transitioning out of the military in the coming years. It is imperative to our government, our institution, and most importantly our patients that efforts are made to develop a more permanent and efficacious treatment application to provide relief to these wounded heroes. This amputee population is unique in that they are younger, healthier, and highly motivated to live as “normal” of a life as possible. The ability to ambulate in a prosthetic device can have a huge social and psychological impact, and providing a therapy that minimizes complications associated with prosthetic use is invaluable. We are excited about the results we have seen with the microwave thermal ablation device and feel that there is potential benefit for other amputee populations if the procedure is perfected.

It is an exciting age in medicine where technology and biology have remarkably honed our diagnostic and treatment capabilities. We hope that everyone in the dermatology community shares our enthusiasm and will continue to explore and test these new technologies to improve and better the lives of the patients we treat.

We live in a time when young, otherwise healthy, active-duty individuals are undergoing traumatic amputations at an exceedingly high rate due to ongoing military engagements. According to US military casualty statistics through September 1, 2014, Operation Iraqi Freedom, Operation Enduring Freedom, and Operation New Dawn veterans have undergone a total of 1573 amputations.¹ Walter Reed National Military Medical Center (WRNMMC) is one of several military facilities that has managed the care of these unique patients returning from the many ongoing conflicts around the globe. Multidisciplinary teams composed of surgeons, anesthesiologists, physical therapists, prosthetists, and others have joined forces to provide extraordinary emergency and recovery care for these patients. Even in the best hands, however, these traumatic amputee patients often experience long-term and lifelong sequelae of their injuries. As dermatologists at this facility (S.P. was at WRNMMC for 3 years before transferring to Madigan Army Medical Center), we are often asked to assist in the management of a subset of these sequelae: residual limb dermatoses. Residual limb dermatoses such as recurrent bacterial and fungal infections, cysts, abrasions, blistering, irritant and allergic dermatitis, pressure ulcers, acroangiodermatitis, stump edema, and many others have a high prevalence in our wounded warrior population and impact both amputee quality of life and utilization of medical resources. As many as 73% of amputees will experience a variety of residual limb dermatoses at some point in their life, with the highest prevalence in younger, more active patients.^2,3 We have observed that many, if not most, of these cutaneous problems can be attributed to or are exacerbated by hyperhidrosis of the residual limb. Hyperhidrosis in this population of patients can be related to excessive sweat production, but more commonly, it is attributed to the lack of evaporation of normal perspiration.

Excess Sweat and the Prosthesis

To understand hyperhidrosis in amputee patients, it is important to understand the anatomy of the prosthesis. There are a variety of materials that are used to create prosthetic limbs. The most commonly used materials are a combination of plastic and carbon graphite/carbon fiber. The modern prosthetic limb uses a suspension system that attaches the prosthetic limb to the residual limb by creating a vacuum. There are several mechanisms to create this vacuum; however, they all depend on a liner that fits snugly over the residual limb. This liner-limb interface is responsible for protection, mitigation of sheering forces, and comfort, and it is the anchor for a good fit in the prosthesis. Unfortunately, this liner is the primary factor contributing to residual limb dermatologic problems. The liner usually is made of silicone or polyurethane and is designed to be water and sweat resistant; any excess water that finds its way into the liner-prosthetic interface will affect the seal of the device and cause slippage of the prosthesis.⁴ This water-resistant barrier is what induces the hyperhidrotic environment over the residual limb that is covered. These patients sweat with exertion, and because of the water-resistant liner, there is no mechanism for sweat evaporation. This leads to a localized environment of hyperhidrosis, increasing patients’ susceptibility to chronic skin conditions. In addition to the dermatologic pathology of the residual limb, there are notable functional concerns caused by excessive sweating. Increased moisture due to sweating not only leads to pathologic dermatoses but also to impaired fit and loss of suction by leaking into the prosthetic-limb interface, which in turn can lead to decreased stamina in the prosthesis, falls, and in severe cases even prosthetic abandonment.⁵

Treating Hyperhidrosis

While working with wounded warriors in the dermatology, prosthetics, and wound care clinics at WRNMMC, it repeatedly became clear that our current treatment options for hyperhidrosis in this population were not routinely tolerated or efficacious. Although hyperhidrosis of the axillary or palmoplantar region is a commonly encountered problem with clear treatment algorithms and management strategies, hyperhidrosis in the setting of a residual limb following amputation is somewhat unique and without definitive permanent cure. In approaching this problem, our institution has implemented a variety of therapies to the residual limb that have been well described and effective in the treatment in the axillary region.

Topical antiperspirants (ie, aluminum chloride) are well-documented treatments of hyperhidrosis and work by the formation of a metal iron precipitate when binding with mucopolysaccharides. These complexes cause damage to epithelial cells lining the ostia of eccrine glands, forming a plug in the lumen of the eccrine duct.⁶ Unfortunately, irritant contact dermatitis has affected the majority of our residual limb patients who have used topical antiperspirants and has led to poor compliance. Glycopyrrolate, an antimuscarinic agent, often is used with varying degrees of success. It works as a competitive antagonist blocking the acetylcholine muscarinic receptors that are responsible for the innervation of eccrine sweat glands. Several of our residual limb patients have a history of global hyperhidrosis and have responded favorably to 1- to 2-mg doses of glycopyrrolate administered twice daily. The side-effect profile headlined by xerostomia, urinary retention, and constipation has, as it often does, limited the dosing. We have observed that with the use of glycopyrrolate, these patients admit to less overall sweating but experience only a mild decrease in the cutaneous problems they experience over the residual limbs, which is likely attributed to the prosthetic liner that induces hyperhidrosis by preventing sweat evaporation from the residual limb. Patients may not be sweating as much, but they are still sweating and that sweat is unable to evaporate from under the liner.

Botulinum toxin is a common treatment of axillary hyperhidrosis and its effects on residual limbs are the same.^5,7 Botulinum toxin types A, B, and E specifically cleave soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, which prevents neurosecretory vesicles from fusing with the interior surface of the plasma membrane of the nerve synapse, thereby blocking release of acetylcholine.⁸ In inhibiting acetylcholine release, the signal for eccrine secretion is blocked. This therapy has been effective in our residual limb patients who tolerate the treatment. It typically involves the injection of 300 to 500 U of botulinum toxin type A diluted with 0.9% saline at 2 to 5 U per 0.1 mL into the residual limb.⁵ As with the other treatments, there are side effects that complicate compliance. Most residual limb treatments require 150 injections, which can be uncomfortable for this patient cohort. The majority of these wounded warriors have abnormal anatomy because of the traumatic nature of their injuries (ie, improvised explosive device attacks, artillery injury), and they often experience hyperesthesia, phantom limb pain, and notable scarring. These injections can be extremely painful, which often limits their utility. In addition, the therapy only provides 3 to 6 months of symptom relief. Our compliance rate for returning patients has not been good and we suspect that it is likely due to the discomfort associated with the injections.

Other therapies such as laser hair removal and iontophoresis have been attempted but have not yielded great results or compliance. In addition to the limitations of these treatment methods, the residual limbs have presented their own unique set of challenges; complications have included varied anatomy of the residual limbs, scarring, sensitivities, and heterotopic ossification. Temporary remedies such as botulinum toxin injections also present logistical complications because they require repetitive procedural appointments that can be quite burdensome to attend when these patients move back home, often far away from our large military treatment facilities.

A New Therapy With Exciting Potential

With the recent advent of microwave thermal ablation technology, the potential for a different, possibly permanent treatment was discovered. Microwave thermal ablation of the eccrine coils has been proven safe and effective in the prolonged reduction of hyperhidrosis of the axillae and has presented as a potential therapy for our residual limb hyperhidrosis patient population. This technology produces heat that is targeted to a specific depth in the treated tissue while cooling the epidermis. There are various treatment levels that can be used to deliver graded intensities of heat. When the deep dermis is targeted, adnexal structures are denatured and destroyed, causing diminished or eliminated function. Eccrine sweat glands, apocrine glands, and even hair follicles are affected by the therapy. The manufacturer of the only microwave thermal ablation device on the market that is approved by the US Food and Drug Administration to treat axillary hyperhidrosis has suggested that these effects are long-term and possibly permanent.⁹ After several iterations with this technology, we have been able to successfully apply microwave thermal ablation of eccrine coils to 5 residual limbs and are excited about the promise that this technique possesses. A report of our index case will be published soon,¹⁰ and we are looking forward to launching our protocol treating traumatic lower extremity amputee patients that have hyperhidrosis with microwave therapy ablation technology here at WRNMMC.

Final Thoughts

Amputation residual limb dermatoses have a high prevalence and impact on amputee quality of life, particularly among young military members who strive to maintain a highly active lifestyle. Many of these dermatoses are directly related to hyperhidrosis of the residual limb that is covered by the prosthetic device and the liner that interfaces with the skin. Although many treatments for residual limb hyperhidrosis have been used with varying efficacy, none have offered a cost-effective or sustained response. Many of our wounded warriors in this amputee population have or will be transitioning out of the military in the coming years. It is imperative to our government, our institution, and most importantly our patients that efforts are made to develop a more permanent and efficacious treatment application to provide relief to these wounded heroes. This amputee population is unique in that they are younger, healthier, and highly motivated to live as “normal” of a life as possible. The ability to ambulate in a prosthetic device can have a huge social and psychological impact, and providing a therapy that minimizes complications associated with prosthetic use is invaluable. We are excited about the results we have seen with the microwave thermal ablation device and feel that there is potential benefit for other amputee populations if the procedure is perfected.

It is an exciting age in medicine where technology and biology have remarkably honed our diagnostic and treatment capabilities. We hope that everyone in the dermatology community shares our enthusiasm and will continue to explore and test these new technologies to improve and better the lives of the patients we treat.

We live in a time when young, otherwise healthy, active-duty individuals are undergoing traumatic amputations at an exceedingly high rate due to ongoing military engagements. According to US military casualty statistics through September 1, 2014, Operation Iraqi Freedom, Operation Enduring Freedom, and Operation New Dawn veterans have undergone a total of 1573 amputations.¹ Walter Reed National Military Medical Center (WRNMMC) is one of several military facilities that has managed the care of these unique patients returning from the many ongoing conflicts around the globe. Multidisciplinary teams composed of surgeons, anesthesiologists, physical therapists, prosthetists, and others have joined forces to provide extraordinary emergency and recovery care for these patients. Even in the best hands, however, these traumatic amputee patients often experience long-term and lifelong sequelae of their injuries. As dermatologists at this facility (S.P. was at WRNMMC for 3 years before transferring to Madigan Army Medical Center), we are often asked to assist in the management of a subset of these sequelae: residual limb dermatoses. Residual limb dermatoses such as recurrent bacterial and fungal infections, cysts, abrasions, blistering, irritant and allergic dermatitis, pressure ulcers, acroangiodermatitis, stump edema, and many others have a high prevalence in our wounded warrior population and impact both amputee quality of life and utilization of medical resources. As many as 73% of amputees will experience a variety of residual limb dermatoses at some point in their life, with the highest prevalence in younger, more active patients.^2,3 We have observed that many, if not most, of these cutaneous problems can be attributed to or are exacerbated by hyperhidrosis of the residual limb. Hyperhidrosis in this population of patients can be related to excessive sweat production, but more commonly, it is attributed to the lack of evaporation of normal perspiration.

Excess Sweat and the Prosthesis

To understand hyperhidrosis in amputee patients, it is important to understand the anatomy of the prosthesis. There are a variety of materials that are used to create prosthetic limbs. The most commonly used materials are a combination of plastic and carbon graphite/carbon fiber. The modern prosthetic limb uses a suspension system that attaches the prosthetic limb to the residual limb by creating a vacuum. There are several mechanisms to create this vacuum; however, they all depend on a liner that fits snugly over the residual limb. This liner-limb interface is responsible for protection, mitigation of sheering forces, and comfort, and it is the anchor for a good fit in the prosthesis. Unfortunately, this liner is the primary factor contributing to residual limb dermatologic problems. The liner usually is made of silicone or polyurethane and is designed to be water and sweat resistant; any excess water that finds its way into the liner-prosthetic interface will affect the seal of the device and cause slippage of the prosthesis.⁴ This water-resistant barrier is what induces the hyperhidrotic environment over the residual limb that is covered. These patients sweat with exertion, and because of the water-resistant liner, there is no mechanism for sweat evaporation. This leads to a localized environment of hyperhidrosis, increasing patients’ susceptibility to chronic skin conditions. In addition to the dermatologic pathology of the residual limb, there are notable functional concerns caused by excessive sweating. Increased moisture due to sweating not only leads to pathologic dermatoses but also to impaired fit and loss of suction by leaking into the prosthetic-limb interface, which in turn can lead to decreased stamina in the prosthesis, falls, and in severe cases even prosthetic abandonment.⁵

Treating Hyperhidrosis

While working with wounded warriors in the dermatology, prosthetics, and wound care clinics at WRNMMC, it repeatedly became clear that our current treatment options for hyperhidrosis in this population were not routinely tolerated or efficacious. Although hyperhidrosis of the axillary or palmoplantar region is a commonly encountered problem with clear treatment algorithms and management strategies, hyperhidrosis in the setting of a residual limb following amputation is somewhat unique and without definitive permanent cure. In approaching this problem, our institution has implemented a variety of therapies to the residual limb that have been well described and effective in the treatment in the axillary region.

Topical antiperspirants (ie, aluminum chloride) are well-documented treatments of hyperhidrosis and work by the formation of a metal iron precipitate when binding with mucopolysaccharides. These complexes cause damage to epithelial cells lining the ostia of eccrine glands, forming a plug in the lumen of the eccrine duct.⁶ Unfortunately, irritant contact dermatitis has affected the majority of our residual limb patients who have used topical antiperspirants and has led to poor compliance. Glycopyrrolate, an antimuscarinic agent, often is used with varying degrees of success. It works as a competitive antagonist blocking the acetylcholine muscarinic receptors that are responsible for the innervation of eccrine sweat glands. Several of our residual limb patients have a history of global hyperhidrosis and have responded favorably to 1- to 2-mg doses of glycopyrrolate administered twice daily. The side-effect profile headlined by xerostomia, urinary retention, and constipation has, as it often does, limited the dosing. We have observed that with the use of glycopyrrolate, these patients admit to less overall sweating but experience only a mild decrease in the cutaneous problems they experience over the residual limbs, which is likely attributed to the prosthetic liner that induces hyperhidrosis by preventing sweat evaporation from the residual limb. Patients may not be sweating as much, but they are still sweating and that sweat is unable to evaporate from under the liner.

Botulinum toxin is a common treatment of axillary hyperhidrosis and its effects on residual limbs are the same.^5,7 Botulinum toxin types A, B, and E specifically cleave soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, which prevents neurosecretory vesicles from fusing with the interior surface of the plasma membrane of the nerve synapse, thereby blocking release of acetylcholine.⁸ In inhibiting acetylcholine release, the signal for eccrine secretion is blocked. This therapy has been effective in our residual limb patients who tolerate the treatment. It typically involves the injection of 300 to 500 U of botulinum toxin type A diluted with 0.9% saline at 2 to 5 U per 0.1 mL into the residual limb.⁵ As with the other treatments, there are side effects that complicate compliance. Most residual limb treatments require 150 injections, which can be uncomfortable for this patient cohort. The majority of these wounded warriors have abnormal anatomy because of the traumatic nature of their injuries (ie, improvised explosive device attacks, artillery injury), and they often experience hyperesthesia, phantom limb pain, and notable scarring. These injections can be extremely painful, which often limits their utility. In addition, the therapy only provides 3 to 6 months of symptom relief. Our compliance rate for returning patients has not been good and we suspect that it is likely due to the discomfort associated with the injections.

Other therapies such as laser hair removal and iontophoresis have been attempted but have not yielded great results or compliance. In addition to the limitations of these treatment methods, the residual limbs have presented their own unique set of challenges; complications have included varied anatomy of the residual limbs, scarring, sensitivities, and heterotopic ossification. Temporary remedies such as botulinum toxin injections also present logistical complications because they require repetitive procedural appointments that can be quite burdensome to attend when these patients move back home, often far away from our large military treatment facilities.

A New Therapy With Exciting Potential

With the recent advent of microwave thermal ablation technology, the potential for a different, possibly permanent treatment was discovered. Microwave thermal ablation of the eccrine coils has been proven safe and effective in the prolonged reduction of hyperhidrosis of the axillae and has presented as a potential therapy for our residual limb hyperhidrosis patient population. This technology produces heat that is targeted to a specific depth in the treated tissue while cooling the epidermis. There are various treatment levels that can be used to deliver graded intensities of heat. When the deep dermis is targeted, adnexal structures are denatured and destroyed, causing diminished or eliminated function. Eccrine sweat glands, apocrine glands, and even hair follicles are affected by the therapy. The manufacturer of the only microwave thermal ablation device on the market that is approved by the US Food and Drug Administration to treat axillary hyperhidrosis has suggested that these effects are long-term and possibly permanent.⁹ After several iterations with this technology, we have been able to successfully apply microwave thermal ablation of eccrine coils to 5 residual limbs and are excited about the promise that this technique possesses. A report of our index case will be published soon,¹⁰ and we are looking forward to launching our protocol treating traumatic lower extremity amputee patients that have hyperhidrosis with microwave therapy ablation technology here at WRNMMC.

Final Thoughts

Amputation residual limb dermatoses have a high prevalence and impact on amputee quality of life, particularly among young military members who strive to maintain a highly active lifestyle. Many of these dermatoses are directly related to hyperhidrosis of the residual limb that is covered by the prosthetic device and the liner that interfaces with the skin. Although many treatments for residual limb hyperhidrosis have been used with varying efficacy, none have offered a cost-effective or sustained response. Many of our wounded warriors in this amputee population have or will be transitioning out of the military in the coming years. It is imperative to our government, our institution, and most importantly our patients that efforts are made to develop a more permanent and efficacious treatment application to provide relief to these wounded heroes. This amputee population is unique in that they are younger, healthier, and highly motivated to live as “normal” of a life as possible. The ability to ambulate in a prosthetic device can have a huge social and psychological impact, and providing a therapy that minimizes complications associated with prosthetic use is invaluable. We are excited about the results we have seen with the microwave thermal ablation device and feel that there is potential benefit for other amputee populations if the procedure is perfected.

It is an exciting age in medicine where technology and biology have remarkably honed our diagnostic and treatment capabilities. We hope that everyone in the dermatology community shares our enthusiasm and will continue to explore and test these new technologies to improve and better the lives of the patients we treat.

CHICAGO – The Metastatic Breast Cancer Project is an innovative direct-to-patient initiative that allows metastatic breast cancer patients from around the country – often found through social media – to enroll themselves into a research study, primary investigator Dr. Nikhil Wagle said at the annual meeting of the American Society of Clinical Oncology.

Patients interested in participating can visit the project’s website and consent themselves into the study. Patients then fill out a questionnaire about their cancer and their treatments and provide a saliva sample using an at-home kit. Meanwhile, researchers obtain medical records and collect portions of stored tumor samples if available. The overarching goal of the project is to expedite metastatic breast cancer (MBC) genomics research by gaining access to a larger pool of patients with MBC and to generate novel research questions. Over 1,100 patients have already enrolled in the study, and many of them fall into groups of patients – such as those with extraordinary response to treatment or those of racial/ethnic minorities – that are normally challenging to capture in traditional studies.

In a video interview, Dr. Wagle of the Dana-Farber Cancer Institute in Boston and the Broad Institute in Cambridge, Mass., summarizes the unique benefits of the project and discusses future plans, which include gathering patient genomic data from blood biopsy samples and expanding the project to other types of cancers.

[email protected]

CHICAGO – The Metastatic Breast Cancer Project is an innovative direct-to-patient initiative that allows metastatic breast cancer patients from around the country – often found through social media – to enroll themselves into a research study, primary investigator Dr. Nikhil Wagle said at the annual meeting of the American Society of Clinical Oncology.

Patients interested in participating can visit the project’s website and consent themselves into the study. Patients then fill out a questionnaire about their cancer and their treatments and provide a saliva sample using an at-home kit. Meanwhile, researchers obtain medical records and collect portions of stored tumor samples if available. The overarching goal of the project is to expedite metastatic breast cancer (MBC) genomics research by gaining access to a larger pool of patients with MBC and to generate novel research questions. Over 1,100 patients have already enrolled in the study, and many of them fall into groups of patients – such as those with extraordinary response to treatment or those of racial/ethnic minorities – that are normally challenging to capture in traditional studies.

In a video interview, Dr. Wagle of the Dana-Farber Cancer Institute in Boston and the Broad Institute in Cambridge, Mass., summarizes the unique benefits of the project and discusses future plans, which include gathering patient genomic data from blood biopsy samples and expanding the project to other types of cancers.

[email protected]

CHICAGO – The Metastatic Breast Cancer Project is an innovative direct-to-patient initiative that allows metastatic breast cancer patients from around the country – often found through social media – to enroll themselves into a research study, primary investigator Dr. Nikhil Wagle said at the annual meeting of the American Society of Clinical Oncology.

Patients interested in participating can visit the project’s website and consent themselves into the study. Patients then fill out a questionnaire about their cancer and their treatments and provide a saliva sample using an at-home kit. Meanwhile, researchers obtain medical records and collect portions of stored tumor samples if available. The overarching goal of the project is to expedite metastatic breast cancer (MBC) genomics research by gaining access to a larger pool of patients with MBC and to generate novel research questions. Over 1,100 patients have already enrolled in the study, and many of them fall into groups of patients – such as those with extraordinary response to treatment or those of racial/ethnic minorities – that are normally challenging to capture in traditional studies.

In a video interview, Dr. Wagle of the Dana-Farber Cancer Institute in Boston and the Broad Institute in Cambridge, Mass., summarizes the unique benefits of the project and discusses future plans, which include gathering patient genomic data from blood biopsy samples and expanding the project to other types of cancers.

[email protected]

Concern that the Hospital Readmissions Reduction Program (HRRP) has led to more observation stays in an effort by hospitals to avoid readmission penalties can be put to rest.

A study published in late February in the New England Journal of Medicine shows that while readmission rates dropped dramatically with the passage of the Affordable Care Act (ACA) in 2010, this drop was not correlated with an increase in observation services within the nearly 4,000 individual hospitals assessed.1

“I think we were all really happy to see this paper because it’s really well done and it confirms what our gut feeling was as hospitalists—that the readmissions rate falling wasn’t linked to the increase in the use of observation stays,” says Ann Sheehy, MD, MS, FHM, a hospitalist at the University of Wisconsin School of Medicine and Public Health and member of SHM’s Public Policy Committee. “The paper definitively shows that hospitals are not gaming the system to avoid readmission penalties.”

Potentially avoidable hospital readmissions within 30 days of discharge were estimated in 2009 to cost Medicare more than $17 billion annually and are considered a mark of poor-quality care.2 The ACA established HRRP to penalize hospitals with higher-than-expected 30-day readmission rates for several targeted conditions: heart failure, pneumonia, COPD, acute myocardial infarction, total hip and knee replacement, and coronary artery bypass graft surgery.

“Readmission rates had been rock stable for years and years, and coincidentally they came down as observation status rose,” says Ashish Jha, MD, MPH, hospitalist at the VA Boston Healthcare System and professor of health policy at the Harvard T.H. Chan School of Public Health. “The concerning part was that we thought we were making care better by reducing readmissions, but if we were just shifting readmissions to observation, that’s not a change in care pattern—that’s a change in the classification of billing data.”

Earlier data, including an article and an analysis in the Health Affairs blog, also suggested hospitals were trading observation for readmissions, Dr. Jha says.3,4 But the new data have assuaged his concern.

“They did it right,” he says. “Previous studies lumped hospitals together in categories and were not carefully teasing apart what individual hospitals were doing, and when they looked at the individual level, we see no correlation.”

The study’s lead author, Rachael Zuckerman, an economist in the U.S. Department of Health & Human Services (HHS) Office of the Assistant Secretary for Planning and Evaluation (ASPE), writes in a blog post that approximately 565,000 readmissions were likely prevented for the program’s original targeted conditions—heart failure, pneumonia, and acute myocardial infarction—between 2010 and 2015, compared to the readmission rates in the year before passage of the ACA.5

The study examined within-hospital rates of readmission and observation stays among Medicare beneficiaries from October 2007 through May 2015. Within hospitals, there was no correlation between the decline in readmission rates and an uptick in observation stays based on more than 7 million and 45 million index stays for targeted conditions and non-targeted conditions, respectively.

Readmission rates for HRRP’s original target conditions dropped from 21.5% to 17.8%, while non-targeted conditions dropped from 15.3% to 13.1%.

The most rapid drop for targeted and non-targeted conditions occurred shortly after the ACA’s passage, from March 2010 until October 2012, particularly within the six-month window from March through September 2010. Readmission penalties began in October 2012, based on three year’s worth of baseline data.

“Hospitals were reporting readmission rates and CMS was publishing them before the ACA was passed,” says study co-author Steven Sheingold, APSE director of healthcare financing policy. “Hospitals had a good idea a year or two earlier whether they might be in a penalty situation.”

Meanwhile, between 2007 and 2015, observation stays for targeted conditions increased from 2.6% to 4.7% and from 2.5% to 4.2% for non-targeted conditions. There was a steady increase across the entire analysis period, with no significant change pre- and post-ACA.

“Readmissions seem to be more related to passage of the Affordable Care Act than observation,” Zuckerman says. Changes in observation rate are likely due to other factors, such as confusion over Medicare recovery audit contractors, the study authors conclude.

Whether the drop in readmission rates without related increase in observation is tied to improved patient health is still unknown, as Dr. Jha explains in his blog, An Ounce of Evidence. He believes it is “flatly incorrect” to assume lower readmission rates mean better patient outcomes “because readmissions are a utilization measure, a measure of integration and accountability, not a patient outcome measure, not a state of health,” he explains.

While the current study does not address this, Zuckerman says her team is interested in understanding whether overall health measures are changing.

“A hospital is not always a bad thing,” Dr. Jha says. “Sometimes they’re just what a patient needs.”

Dr. Sheehy is particularly interested in why, after October 2012, the steep drop in readmissions slowed down. Probably, she says, much of the low hanging fruit was plucked. But it suggests there is still a population of patients facing higher-than-expected readmissions, and researchers would be wise to understand who they are and how they might be better served.

“The next step is looking at people who are still being readmitted,” she says. TH

Kelly April Tyrell is a freelance writer in Madison, Wis.

References

1. Zuckerman RB, Sheingold SH, Orav EJ, Ruhter J, Epstein AM. Readmissions, observation, and the Hospital Readmissions Reduction Program [published online ahead of print April 21, 2016]. N Engl J Med. doi:10.1056/NEJMsa1513024.
2. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service program. N Engl J Med. 2009;360(14):1418-1428.
3. Himmelstein D, Woolhandler S. Quality improvement: ‘become good at cheating and you never need to become good at anything else.’ Available at: http://healthaffairs.org/blog/2015/08/27/quality-improvement-become-good-at-cheating-and-you-never-need-to-become-good-at-anything-else/. Published August 27, 2015. Accessed April 15, 2016.
4. Noel-Miller C, Lind K. Is observation status substituting for hospital readmission? Available at: http://healthaffairs.org/blog/2015/10/28/is-observation-status-substituting-for-hospital-readmission/. Published October 25, 2016. Accessed April 15, 2016.
5. Zuckerman R. Reducing avoidable hospital readmissions to create a better, safer health care system. Available at: http://www.hhs.gov/blog/2016/02/24/reducing-avoidable-hospital-readmissions.html. Published February 24, 2016. Accessed April 15, 2016.

Concern that the Hospital Readmissions Reduction Program (HRRP) has led to more observation stays in an effort by hospitals to avoid readmission penalties can be put to rest.

A study published in late February in the New England Journal of Medicine shows that while readmission rates dropped dramatically with the passage of the Affordable Care Act (ACA) in 2010, this drop was not correlated with an increase in observation services within the nearly 4,000 individual hospitals assessed.1

“I think we were all really happy to see this paper because it’s really well done and it confirms what our gut feeling was as hospitalists—that the readmissions rate falling wasn’t linked to the increase in the use of observation stays,” says Ann Sheehy, MD, MS, FHM, a hospitalist at the University of Wisconsin School of Medicine and Public Health and member of SHM’s Public Policy Committee. “The paper definitively shows that hospitals are not gaming the system to avoid readmission penalties.”

Potentially avoidable hospital readmissions within 30 days of discharge were estimated in 2009 to cost Medicare more than $17 billion annually and are considered a mark of poor-quality care.2 The ACA established HRRP to penalize hospitals with higher-than-expected 30-day readmission rates for several targeted conditions: heart failure, pneumonia, COPD, acute myocardial infarction, total hip and knee replacement, and coronary artery bypass graft surgery.

“Readmission rates had been rock stable for years and years, and coincidentally they came down as observation status rose,” says Ashish Jha, MD, MPH, hospitalist at the VA Boston Healthcare System and professor of health policy at the Harvard T.H. Chan School of Public Health. “The concerning part was that we thought we were making care better by reducing readmissions, but if we were just shifting readmissions to observation, that’s not a change in care pattern—that’s a change in the classification of billing data.”

Earlier data, including an article and an analysis in the Health Affairs blog, also suggested hospitals were trading observation for readmissions, Dr. Jha says.3,4 But the new data have assuaged his concern.

“They did it right,” he says. “Previous studies lumped hospitals together in categories and were not carefully teasing apart what individual hospitals were doing, and when they looked at the individual level, we see no correlation.”

The study’s lead author, Rachael Zuckerman, an economist in the U.S. Department of Health & Human Services (HHS) Office of the Assistant Secretary for Planning and Evaluation (ASPE), writes in a blog post that approximately 565,000 readmissions were likely prevented for the program’s original targeted conditions—heart failure, pneumonia, and acute myocardial infarction—between 2010 and 2015, compared to the readmission rates in the year before passage of the ACA.5

The study examined within-hospital rates of readmission and observation stays among Medicare beneficiaries from October 2007 through May 2015. Within hospitals, there was no correlation between the decline in readmission rates and an uptick in observation stays based on more than 7 million and 45 million index stays for targeted conditions and non-targeted conditions, respectively.

Readmission rates for HRRP’s original target conditions dropped from 21.5% to 17.8%, while non-targeted conditions dropped from 15.3% to 13.1%.

The most rapid drop for targeted and non-targeted conditions occurred shortly after the ACA’s passage, from March 2010 until October 2012, particularly within the six-month window from March through September 2010. Readmission penalties began in October 2012, based on three year’s worth of baseline data.

“Hospitals were reporting readmission rates and CMS was publishing them before the ACA was passed,” says study co-author Steven Sheingold, APSE director of healthcare financing policy. “Hospitals had a good idea a year or two earlier whether they might be in a penalty situation.”

Meanwhile, between 2007 and 2015, observation stays for targeted conditions increased from 2.6% to 4.7% and from 2.5% to 4.2% for non-targeted conditions. There was a steady increase across the entire analysis period, with no significant change pre- and post-ACA.

“Readmissions seem to be more related to passage of the Affordable Care Act than observation,” Zuckerman says. Changes in observation rate are likely due to other factors, such as confusion over Medicare recovery audit contractors, the study authors conclude.

Whether the drop in readmission rates without related increase in observation is tied to improved patient health is still unknown, as Dr. Jha explains in his blog, An Ounce of Evidence. He believes it is “flatly incorrect” to assume lower readmission rates mean better patient outcomes “because readmissions are a utilization measure, a measure of integration and accountability, not a patient outcome measure, not a state of health,” he explains.

While the current study does not address this, Zuckerman says her team is interested in understanding whether overall health measures are changing.

“A hospital is not always a bad thing,” Dr. Jha says. “Sometimes they’re just what a patient needs.”

Dr. Sheehy is particularly interested in why, after October 2012, the steep drop in readmissions slowed down. Probably, she says, much of the low hanging fruit was plucked. But it suggests there is still a population of patients facing higher-than-expected readmissions, and researchers would be wise to understand who they are and how they might be better served.

“The next step is looking at people who are still being readmitted,” she says. TH

Kelly April Tyrell is a freelance writer in Madison, Wis.

References

1. Zuckerman RB, Sheingold SH, Orav EJ, Ruhter J, Epstein AM. Readmissions, observation, and the Hospital Readmissions Reduction Program [published online ahead of print April 21, 2016]. N Engl J Med. doi:10.1056/NEJMsa1513024.
2. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service program. N Engl J Med. 2009;360(14):1418-1428.
3. Himmelstein D, Woolhandler S. Quality improvement: ‘become good at cheating and you never need to become good at anything else.’ Available at: http://healthaffairs.org/blog/2015/08/27/quality-improvement-become-good-at-cheating-and-you-never-need-to-become-good-at-anything-else/. Published August 27, 2015. Accessed April 15, 2016.
4. Noel-Miller C, Lind K. Is observation status substituting for hospital readmission? Available at: http://healthaffairs.org/blog/2015/10/28/is-observation-status-substituting-for-hospital-readmission/. Published October 25, 2016. Accessed April 15, 2016.
5. Zuckerman R. Reducing avoidable hospital readmissions to create a better, safer health care system. Available at: http://www.hhs.gov/blog/2016/02/24/reducing-avoidable-hospital-readmissions.html. Published February 24, 2016. Accessed April 15, 2016.

Concern that the Hospital Readmissions Reduction Program (HRRP) has led to more observation stays in an effort by hospitals to avoid readmission penalties can be put to rest.

A study published in late February in the New England Journal of Medicine shows that while readmission rates dropped dramatically with the passage of the Affordable Care Act (ACA) in 2010, this drop was not correlated with an increase in observation services within the nearly 4,000 individual hospitals assessed.1

“I think we were all really happy to see this paper because it’s really well done and it confirms what our gut feeling was as hospitalists—that the readmissions rate falling wasn’t linked to the increase in the use of observation stays,” says Ann Sheehy, MD, MS, FHM, a hospitalist at the University of Wisconsin School of Medicine and Public Health and member of SHM’s Public Policy Committee. “The paper definitively shows that hospitals are not gaming the system to avoid readmission penalties.”

Potentially avoidable hospital readmissions within 30 days of discharge were estimated in 2009 to cost Medicare more than $17 billion annually and are considered a mark of poor-quality care.2 The ACA established HRRP to penalize hospitals with higher-than-expected 30-day readmission rates for several targeted conditions: heart failure, pneumonia, COPD, acute myocardial infarction, total hip and knee replacement, and coronary artery bypass graft surgery.

“Readmission rates had been rock stable for years and years, and coincidentally they came down as observation status rose,” says Ashish Jha, MD, MPH, hospitalist at the VA Boston Healthcare System and professor of health policy at the Harvard T.H. Chan School of Public Health. “The concerning part was that we thought we were making care better by reducing readmissions, but if we were just shifting readmissions to observation, that’s not a change in care pattern—that’s a change in the classification of billing data.”

Earlier data, including an article and an analysis in the Health Affairs blog, also suggested hospitals were trading observation for readmissions, Dr. Jha says.3,4 But the new data have assuaged his concern.

“They did it right,” he says. “Previous studies lumped hospitals together in categories and were not carefully teasing apart what individual hospitals were doing, and when they looked at the individual level, we see no correlation.”

The study’s lead author, Rachael Zuckerman, an economist in the U.S. Department of Health & Human Services (HHS) Office of the Assistant Secretary for Planning and Evaluation (ASPE), writes in a blog post that approximately 565,000 readmissions were likely prevented for the program’s original targeted conditions—heart failure, pneumonia, and acute myocardial infarction—between 2010 and 2015, compared to the readmission rates in the year before passage of the ACA.5

The study examined within-hospital rates of readmission and observation stays among Medicare beneficiaries from October 2007 through May 2015. Within hospitals, there was no correlation between the decline in readmission rates and an uptick in observation stays based on more than 7 million and 45 million index stays for targeted conditions and non-targeted conditions, respectively.

Readmission rates for HRRP’s original target conditions dropped from 21.5% to 17.8%, while non-targeted conditions dropped from 15.3% to 13.1%.

The most rapid drop for targeted and non-targeted conditions occurred shortly after the ACA’s passage, from March 2010 until October 2012, particularly within the six-month window from March through September 2010. Readmission penalties began in October 2012, based on three year’s worth of baseline data.

“Hospitals were reporting readmission rates and CMS was publishing them before the ACA was passed,” says study co-author Steven Sheingold, APSE director of healthcare financing policy. “Hospitals had a good idea a year or two earlier whether they might be in a penalty situation.”

Meanwhile, between 2007 and 2015, observation stays for targeted conditions increased from 2.6% to 4.7% and from 2.5% to 4.2% for non-targeted conditions. There was a steady increase across the entire analysis period, with no significant change pre- and post-ACA.

“Readmissions seem to be more related to passage of the Affordable Care Act than observation,” Zuckerman says. Changes in observation rate are likely due to other factors, such as confusion over Medicare recovery audit contractors, the study authors conclude.

Whether the drop in readmission rates without related increase in observation is tied to improved patient health is still unknown, as Dr. Jha explains in his blog, An Ounce of Evidence. He believes it is “flatly incorrect” to assume lower readmission rates mean better patient outcomes “because readmissions are a utilization measure, a measure of integration and accountability, not a patient outcome measure, not a state of health,” he explains.

While the current study does not address this, Zuckerman says her team is interested in understanding whether overall health measures are changing.

“A hospital is not always a bad thing,” Dr. Jha says. “Sometimes they’re just what a patient needs.”

Dr. Sheehy is particularly interested in why, after October 2012, the steep drop in readmissions slowed down. Probably, she says, much of the low hanging fruit was plucked. But it suggests there is still a population of patients facing higher-than-expected readmissions, and researchers would be wise to understand who they are and how they might be better served.

“The next step is looking at people who are still being readmitted,” she says. TH

Kelly April Tyrell is a freelance writer in Madison, Wis.

References

1. Zuckerman RB, Sheingold SH, Orav EJ, Ruhter J, Epstein AM. Readmissions, observation, and the Hospital Readmissions Reduction Program [published online ahead of print April 21, 2016]. N Engl J Med. doi:10.1056/NEJMsa1513024.
2. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service program. N Engl J Med. 2009;360(14):1418-1428.
3. Himmelstein D, Woolhandler S. Quality improvement: ‘become good at cheating and you never need to become good at anything else.’ Available at: http://healthaffairs.org/blog/2015/08/27/quality-improvement-become-good-at-cheating-and-you-never-need-to-become-good-at-anything-else/. Published August 27, 2015. Accessed April 15, 2016.
4. Noel-Miller C, Lind K. Is observation status substituting for hospital readmission? Available at: http://healthaffairs.org/blog/2015/10/28/is-observation-status-substituting-for-hospital-readmission/. Published October 25, 2016. Accessed April 15, 2016.
5. Zuckerman R. Reducing avoidable hospital readmissions to create a better, safer health care system. Available at: http://www.hhs.gov/blog/2016/02/24/reducing-avoidable-hospital-readmissions.html. Published February 24, 2016. Accessed April 15, 2016.

Antonio Palumbo, MD

CHICAGO—The addition of the monoclonal antibody daratumumab to bortezomib and dexamethasone, the current standard of care for relapsed/refractory multiple myeloma (MM), has achieved progression-free survival that is “unprecedented in randomized studies that compared novel treatment” for this disease, according to Antonio Palumbo, MD, lead author of the phase 3 CASTOR study.

Dr Palumbo, of the University of Torino in Torino, Italy, presented the results on behalf of the CASTOR investigators during the plenary session of the 2016 ASCO Annual Meeting (abstract LBA4).

Daratumumab (Darzalex) is a human CD38 monoclonal antibody, which means it is targeted very specifically to the most relevant tumor antigen for plasma cells.

It also has direct major cytotoxic activity through the complement, which translates into major tumor reduction and a profound cytoreduction, Dr Palumbo said.

Even more important, he added, is that this is an immunomodulatory agent able to both increase the T-cell activity in the immune system, which controls the tumor, and also reduce the immunosuppressive regulatory cells that are suppressing the activity of the immune system.

Daratumumab is already approved by the US Food and Drug Administration and conditionally approved by the European Commission as a single agent for the treatment of relapsed/refractory multiple myeloma.

Study design

The CASTOR study was a multicenter, randomized, open-label, active-controlled phase 3 study.

Patients were eligible to enroll if they had relapsed or refractory MM with at least 1 prior line of therapy, which could include prior treatment with bortezomib, but they were not eligible if they were refractory to it.

Investigators randomized 251 patients to the experimental arm of daratumumab, bortezomib (Velcade), and dexamethasone (DVd) and 247 to the control arm of bortezomib and dexamethasone (Vd).

The dosing schedule was the same in both arms for bortezomib and dexamethasone. Patients in the experimental arm received daratumumab (16 mg/kg IV) every week for the first 3 cycles, on day 1 of cycles 4 – 8, and then every 4 weeks until progression.

The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints included time to progression (TTP), overall survival (OS), overall response rate (ORR), very good partial response (VGPR), complete response (CR), minimal residual disease (MRD), time to response, and duration of response.

Patient demographics

Overall, patients had advanced stage disease with a long history of prior treatment.

They were a median age of 64 in both groups, and the time from diagnosis was a median 3.87 years in the experimental arm and 3.72 years in the control arm.

About 60% in both groups had had prior autologous stem cell transplant. Seventy-one percent in the experimental arm and 80% in the control arm had received a prior immunomodulatory drug, and 30% in the experimental arm and 34% in the control arm were refractory to their last line of therapy.

Dr Palumbo pointed out that accrual for the trial was rapid; 500 patients enrolled in 1 year, from September 2014 to September 2015.

“After 3 months, we already saw a difference in terms of efficacy,” he added, and the trial was stopped early. “So the median follow-up is short for this reason,” he explained, “and is around 7 months.”

The discontinuation rate was “as expected,” he said, “higher in the control arm,” with 44% discontinuing compared with 31% in the experimental arm.

Discontinuation for progressive disease was 25% in the control arm and 19% in the experimental arm, “showing already an advantage for the novel combination.”

Adverse events as reasons for discontinuation were 8% in the experimental arm and 10% in the control arm, “showing that the new agent is not adding any extra toxicity to the combination of bortezomib and dexamethasone.”

Efficacy

The “unprecedented” PFS, with a hazard ratio (HR) of 0.39 (95% CI, 0.28-0.53; P<0.0001), translated into a 61% reduction in the risk of disease progression or death for the experimental arm compared with the control arm.

The median PFS was not yet reached in the experimental arm, while the median PFS was 7.2 months in the control arm.

At 1 year, the PFS was 26.9% in the control arm and 60.7% in the experimental arm, “and this translates into a doubling in terms of remission duration for those patients,” Dr Palumbo stated.

“Even better was the outcome for the time to progression,” he said, with an HR of 0.30, “which means a 70% reduction in the risk of disease progression for DVd versus Vd, a more than doubling of time to disease progression.”

PFS by subgroup analysis showed that early intervention with daratumumab maximizes the efficacy of the combination.

For those patients who had received only 1 line of prior treatment, the HR was 0.31 (95% CI, 0.18 – 0.52; P<0.0001), which translated to a 69% reduction in the risk of progression or death for DVd compared with Vd.

The overall response rate revealed the profound cytoreduction achieved by the addition of daratumumab.

The CR rate increased from 9% in the control group to 19% in the experimental arm (P=0.0012), and the VGPR increased from 29% to 59%, in the control and experimental arms, respectively.

“So there is a doubling in the rate of CR and VGPR,” Dr Palumbo pointed out, “and this is quite relevant because more patients do achieve a profound cytoreduction.”

The rate of MRD negativity was 5 times higher for daratumumab-treated patients. Three percent of patients in the control arm were MRD negative (10^-4) compared with 14% in the experimental arm.

Time to response, “in my opinion, is an important issue because . . .  you can reach PR in around 1 month [with DVd] and this is clinically relevant because those patients are symptomatic,” he explained. “Reaching PR in 1 month means getting rid of pain in a quick way.”

“On the other hand, the achieving of CR requires a prolonged treatment,” he added. “CR is being achieved after 12 months of therapy, and MRD negativity might need even longer treatment.”

Safety

Daratumumab-treated patients experienced more thrombocytopenia and peripheral neuropathy (PN) of any grade than the control arm, 47% compared with 38%, respectively.

“But this is not due to the addition of the third agent,” Dr Palumbo clarified. “This is mainly the consequence, in the experimental arm, that treatment with bortezomib was longer in comparison to the control arm, and therefore, the typical toxicity of bortezomib—thrombocytopenia and PN—were slightly higher.”

There was also an increase in upper respiratory tract infections and cough in daratumumab-treated patients.

Grade 3-4 treatment-emergent adverse events occurring in more than 5% of patients included thrombocytopenia, anemia, neutropenia, lymphopenia, pneumonia, hypertension, and sensory PN.

However, grade 4 thrombocyotpenia, Dr Palumbo noted, did not translate into an increase in bleeding.

The major increase in toxicity due to daratumumab was in infusion-related reactions (IRRs), which occurred in 45% of patients. IRRs were consistent with the infusion of other monoclonal antibodies in cancer patients, he said, and 98% of patients with IRRs experienced them on the first infusion.

Conclusions

Dr Palumbo stressed that daratumumab did not increase the cumulative toxicity or the toxicity of the bortezomib-dexamethasone combination.

Daratumumab significantly improved PFS and the response rate; the experimental combination was associated with a 61% reduction in the risk of progression or death.

The benefit was maintained across different subgroups—whether younger, older, good prognosis, bad prognosis, previously exposed to bortezomib or not exposed to bortezomib.

And DVd doubled both VGPR rates and CR rates.

In a press briefing, Dr Palumbo said that in the myeloma field, “we hope to have our R-CHOP, that has been a major treatment for lymphoma now also available with a different antibody for multiple myeloma.”

So the final conclusion, he added, is that “daratumumab-Vd might be considered today a new standard of care for relapsed and refractory multiple myeloma.”

The study was funded by Janssen Research & Development.

Antonio Palumbo, MD

CHICAGO—The addition of the monoclonal antibody daratumumab to bortezomib and dexamethasone, the current standard of care for relapsed/refractory multiple myeloma (MM), has achieved progression-free survival that is “unprecedented in randomized studies that compared novel treatment” for this disease, according to Antonio Palumbo, MD, lead author of the phase 3 CASTOR study.

Dr Palumbo, of the University of Torino in Torino, Italy, presented the results on behalf of the CASTOR investigators during the plenary session of the 2016 ASCO Annual Meeting (abstract LBA4).

Daratumumab (Darzalex) is a human CD38 monoclonal antibody, which means it is targeted very specifically to the most relevant tumor antigen for plasma cells.

It also has direct major cytotoxic activity through the complement, which translates into major tumor reduction and a profound cytoreduction, Dr Palumbo said.

Even more important, he added, is that this is an immunomodulatory agent able to both increase the T-cell activity in the immune system, which controls the tumor, and also reduce the immunosuppressive regulatory cells that are suppressing the activity of the immune system.

Daratumumab is already approved by the US Food and Drug Administration and conditionally approved by the European Commission as a single agent for the treatment of relapsed/refractory multiple myeloma.

Study design

The CASTOR study was a multicenter, randomized, open-label, active-controlled phase 3 study.

Patients were eligible to enroll if they had relapsed or refractory MM with at least 1 prior line of therapy, which could include prior treatment with bortezomib, but they were not eligible if they were refractory to it.

Investigators randomized 251 patients to the experimental arm of daratumumab, bortezomib (Velcade), and dexamethasone (DVd) and 247 to the control arm of bortezomib and dexamethasone (Vd).

The dosing schedule was the same in both arms for bortezomib and dexamethasone. Patients in the experimental arm received daratumumab (16 mg/kg IV) every week for the first 3 cycles, on day 1 of cycles 4 – 8, and then every 4 weeks until progression.

The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints included time to progression (TTP), overall survival (OS), overall response rate (ORR), very good partial response (VGPR), complete response (CR), minimal residual disease (MRD), time to response, and duration of response.

Patient demographics

Overall, patients had advanced stage disease with a long history of prior treatment.

They were a median age of 64 in both groups, and the time from diagnosis was a median 3.87 years in the experimental arm and 3.72 years in the control arm.

About 60% in both groups had had prior autologous stem cell transplant. Seventy-one percent in the experimental arm and 80% in the control arm had received a prior immunomodulatory drug, and 30% in the experimental arm and 34% in the control arm were refractory to their last line of therapy.

Dr Palumbo pointed out that accrual for the trial was rapid; 500 patients enrolled in 1 year, from September 2014 to September 2015.

“After 3 months, we already saw a difference in terms of efficacy,” he added, and the trial was stopped early. “So the median follow-up is short for this reason,” he explained, “and is around 7 months.”

The discontinuation rate was “as expected,” he said, “higher in the control arm,” with 44% discontinuing compared with 31% in the experimental arm.

Discontinuation for progressive disease was 25% in the control arm and 19% in the experimental arm, “showing already an advantage for the novel combination.”

Adverse events as reasons for discontinuation were 8% in the experimental arm and 10% in the control arm, “showing that the new agent is not adding any extra toxicity to the combination of bortezomib and dexamethasone.”

Efficacy

The “unprecedented” PFS, with a hazard ratio (HR) of 0.39 (95% CI, 0.28-0.53; P<0.0001), translated into a 61% reduction in the risk of disease progression or death for the experimental arm compared with the control arm.

The median PFS was not yet reached in the experimental arm, while the median PFS was 7.2 months in the control arm.

At 1 year, the PFS was 26.9% in the control arm and 60.7% in the experimental arm, “and this translates into a doubling in terms of remission duration for those patients,” Dr Palumbo stated.

“Even better was the outcome for the time to progression,” he said, with an HR of 0.30, “which means a 70% reduction in the risk of disease progression for DVd versus Vd, a more than doubling of time to disease progression.”

PFS by subgroup analysis showed that early intervention with daratumumab maximizes the efficacy of the combination.

For those patients who had received only 1 line of prior treatment, the HR was 0.31 (95% CI, 0.18 – 0.52; P<0.0001), which translated to a 69% reduction in the risk of progression or death for DVd compared with Vd.

The overall response rate revealed the profound cytoreduction achieved by the addition of daratumumab.

The CR rate increased from 9% in the control group to 19% in the experimental arm (P=0.0012), and the VGPR increased from 29% to 59%, in the control and experimental arms, respectively.

“So there is a doubling in the rate of CR and VGPR,” Dr Palumbo pointed out, “and this is quite relevant because more patients do achieve a profound cytoreduction.”

The rate of MRD negativity was 5 times higher for daratumumab-treated patients. Three percent of patients in the control arm were MRD negative (10^-4) compared with 14% in the experimental arm.

Time to response, “in my opinion, is an important issue because . . .  you can reach PR in around 1 month [with DVd] and this is clinically relevant because those patients are symptomatic,” he explained. “Reaching PR in 1 month means getting rid of pain in a quick way.”

“On the other hand, the achieving of CR requires a prolonged treatment,” he added. “CR is being achieved after 12 months of therapy, and MRD negativity might need even longer treatment.”

Safety

Daratumumab-treated patients experienced more thrombocytopenia and peripheral neuropathy (PN) of any grade than the control arm, 47% compared with 38%, respectively.

“But this is not due to the addition of the third agent,” Dr Palumbo clarified. “This is mainly the consequence, in the experimental arm, that treatment with bortezomib was longer in comparison to the control arm, and therefore, the typical toxicity of bortezomib—thrombocytopenia and PN—were slightly higher.”

There was also an increase in upper respiratory tract infections and cough in daratumumab-treated patients.

Grade 3-4 treatment-emergent adverse events occurring in more than 5% of patients included thrombocytopenia, anemia, neutropenia, lymphopenia, pneumonia, hypertension, and sensory PN.

However, grade 4 thrombocyotpenia, Dr Palumbo noted, did not translate into an increase in bleeding.

The major increase in toxicity due to daratumumab was in infusion-related reactions (IRRs), which occurred in 45% of patients. IRRs were consistent with the infusion of other monoclonal antibodies in cancer patients, he said, and 98% of patients with IRRs experienced them on the first infusion.

Conclusions

Dr Palumbo stressed that daratumumab did not increase the cumulative toxicity or the toxicity of the bortezomib-dexamethasone combination.

Daratumumab significantly improved PFS and the response rate; the experimental combination was associated with a 61% reduction in the risk of progression or death.

The benefit was maintained across different subgroups—whether younger, older, good prognosis, bad prognosis, previously exposed to bortezomib or not exposed to bortezomib.

And DVd doubled both VGPR rates and CR rates.

In a press briefing, Dr Palumbo said that in the myeloma field, “we hope to have our R-CHOP, that has been a major treatment for lymphoma now also available with a different antibody for multiple myeloma.”

So the final conclusion, he added, is that “daratumumab-Vd might be considered today a new standard of care for relapsed and refractory multiple myeloma.”

The study was funded by Janssen Research & Development.

Antonio Palumbo, MD

CHICAGO—The addition of the monoclonal antibody daratumumab to bortezomib and dexamethasone, the current standard of care for relapsed/refractory multiple myeloma (MM), has achieved progression-free survival that is “unprecedented in randomized studies that compared novel treatment” for this disease, according to Antonio Palumbo, MD, lead author of the phase 3 CASTOR study.

Dr Palumbo, of the University of Torino in Torino, Italy, presented the results on behalf of the CASTOR investigators during the plenary session of the 2016 ASCO Annual Meeting (abstract LBA4).

Daratumumab (Darzalex) is a human CD38 monoclonal antibody, which means it is targeted very specifically to the most relevant tumor antigen for plasma cells.

It also has direct major cytotoxic activity through the complement, which translates into major tumor reduction and a profound cytoreduction, Dr Palumbo said.

Even more important, he added, is that this is an immunomodulatory agent able to both increase the T-cell activity in the immune system, which controls the tumor, and also reduce the immunosuppressive regulatory cells that are suppressing the activity of the immune system.

Daratumumab is already approved by the US Food and Drug Administration and conditionally approved by the European Commission as a single agent for the treatment of relapsed/refractory multiple myeloma.

Study design

The CASTOR study was a multicenter, randomized, open-label, active-controlled phase 3 study.

Patients were eligible to enroll if they had relapsed or refractory MM with at least 1 prior line of therapy, which could include prior treatment with bortezomib, but they were not eligible if they were refractory to it.

Investigators randomized 251 patients to the experimental arm of daratumumab, bortezomib (Velcade), and dexamethasone (DVd) and 247 to the control arm of bortezomib and dexamethasone (Vd).

The dosing schedule was the same in both arms for bortezomib and dexamethasone. Patients in the experimental arm received daratumumab (16 mg/kg IV) every week for the first 3 cycles, on day 1 of cycles 4 – 8, and then every 4 weeks until progression.

The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints included time to progression (TTP), overall survival (OS), overall response rate (ORR), very good partial response (VGPR), complete response (CR), minimal residual disease (MRD), time to response, and duration of response.

Patient demographics

Overall, patients had advanced stage disease with a long history of prior treatment.

They were a median age of 64 in both groups, and the time from diagnosis was a median 3.87 years in the experimental arm and 3.72 years in the control arm.

About 60% in both groups had had prior autologous stem cell transplant. Seventy-one percent in the experimental arm and 80% in the control arm had received a prior immunomodulatory drug, and 30% in the experimental arm and 34% in the control arm were refractory to their last line of therapy.

Dr Palumbo pointed out that accrual for the trial was rapid; 500 patients enrolled in 1 year, from September 2014 to September 2015.

“After 3 months, we already saw a difference in terms of efficacy,” he added, and the trial was stopped early. “So the median follow-up is short for this reason,” he explained, “and is around 7 months.”

The discontinuation rate was “as expected,” he said, “higher in the control arm,” with 44% discontinuing compared with 31% in the experimental arm.

Discontinuation for progressive disease was 25% in the control arm and 19% in the experimental arm, “showing already an advantage for the novel combination.”

Adverse events as reasons for discontinuation were 8% in the experimental arm and 10% in the control arm, “showing that the new agent is not adding any extra toxicity to the combination of bortezomib and dexamethasone.”

Efficacy

The “unprecedented” PFS, with a hazard ratio (HR) of 0.39 (95% CI, 0.28-0.53; P<0.0001), translated into a 61% reduction in the risk of disease progression or death for the experimental arm compared with the control arm.

The median PFS was not yet reached in the experimental arm, while the median PFS was 7.2 months in the control arm.

At 1 year, the PFS was 26.9% in the control arm and 60.7% in the experimental arm, “and this translates into a doubling in terms of remission duration for those patients,” Dr Palumbo stated.

“Even better was the outcome for the time to progression,” he said, with an HR of 0.30, “which means a 70% reduction in the risk of disease progression for DVd versus Vd, a more than doubling of time to disease progression.”

PFS by subgroup analysis showed that early intervention with daratumumab maximizes the efficacy of the combination.

For those patients who had received only 1 line of prior treatment, the HR was 0.31 (95% CI, 0.18 – 0.52; P<0.0001), which translated to a 69% reduction in the risk of progression or death for DVd compared with Vd.

The overall response rate revealed the profound cytoreduction achieved by the addition of daratumumab.

The CR rate increased from 9% in the control group to 19% in the experimental arm (P=0.0012), and the VGPR increased from 29% to 59%, in the control and experimental arms, respectively.

“So there is a doubling in the rate of CR and VGPR,” Dr Palumbo pointed out, “and this is quite relevant because more patients do achieve a profound cytoreduction.”

The rate of MRD negativity was 5 times higher for daratumumab-treated patients. Three percent of patients in the control arm were MRD negative (10^-4) compared with 14% in the experimental arm.

Time to response, “in my opinion, is an important issue because . . .  you can reach PR in around 1 month [with DVd] and this is clinically relevant because those patients are symptomatic,” he explained. “Reaching PR in 1 month means getting rid of pain in a quick way.”

“On the other hand, the achieving of CR requires a prolonged treatment,” he added. “CR is being achieved after 12 months of therapy, and MRD negativity might need even longer treatment.”

Safety

Daratumumab-treated patients experienced more thrombocytopenia and peripheral neuropathy (PN) of any grade than the control arm, 47% compared with 38%, respectively.

“But this is not due to the addition of the third agent,” Dr Palumbo clarified. “This is mainly the consequence, in the experimental arm, that treatment with bortezomib was longer in comparison to the control arm, and therefore, the typical toxicity of bortezomib—thrombocytopenia and PN—were slightly higher.”

There was also an increase in upper respiratory tract infections and cough in daratumumab-treated patients.

Grade 3-4 treatment-emergent adverse events occurring in more than 5% of patients included thrombocytopenia, anemia, neutropenia, lymphopenia, pneumonia, hypertension, and sensory PN.

However, grade 4 thrombocyotpenia, Dr Palumbo noted, did not translate into an increase in bleeding.

The major increase in toxicity due to daratumumab was in infusion-related reactions (IRRs), which occurred in 45% of patients. IRRs were consistent with the infusion of other monoclonal antibodies in cancer patients, he said, and 98% of patients with IRRs experienced them on the first infusion.

Conclusions

Dr Palumbo stressed that daratumumab did not increase the cumulative toxicity or the toxicity of the bortezomib-dexamethasone combination.

Daratumumab significantly improved PFS and the response rate; the experimental combination was associated with a 61% reduction in the risk of progression or death.

The benefit was maintained across different subgroups—whether younger, older, good prognosis, bad prognosis, previously exposed to bortezomib or not exposed to bortezomib.

And DVd doubled both VGPR rates and CR rates.

In a press briefing, Dr Palumbo said that in the myeloma field, “we hope to have our R-CHOP, that has been a major treatment for lymphoma now also available with a different antibody for multiple myeloma.”

So the final conclusion, he added, is that “daratumumab-Vd might be considered today a new standard of care for relapsed and refractory multiple myeloma.”

The study was funded by Janssen Research & Development.

Poster session at ASCO 2016

© ASCO/Zach Boyden-Holmes

CHICAGO—Hispanic white and non-Hispanic black adolescents and young adults (AYA) are more likely to die of their disease than the same-aged white patients, according to a study presented at the 2016 ASCO Annual Meeting.

If the chance of a young-adult white patient dying within 2 years of receiving a liver cancer diagnosis is a baseline of 1, the chance of a similar Hispanic white patient dying is 1.77 and a non-Hispanic black patient's chance of dying is 1.76.

And this holds true across cancer types, including germ cell tumors, soft tissue sarcomas, lymphomas, and leukemias.

"What this means is that black and Hispanic young adult patients are almost 75% more likely to die after being diagnosed with liver cancer than are white young adult patients," said co-investigator Meryl Colton, a medical student at the University of Colorado.

Using data from the Surveillance, Epidemiologic and End Results (SEER) database, Colton and Adam L. Green, MD, of Children’s Hospital Colorado in Aurora, compared adolescents and young adults between the ages of 15 and 29 to evaluate racial/ethnic disparities in this age population, which is at particular risk for disparities in socioeconomic status and delayed diagnosis.

Even after controlling for insurance status and stage at diagnosis, the researchers determined that there were disparities in death rates for Hispanic whites, non-Hispanic blacks, and Hispanic blacks.

This implies that there is an influence of race/ethnicity independent of financial resources.

For leukemia, the hazard ratio was 1.15 for Hispanic whites and 1.05 for non-Hispanic blacks compared with non-Hispanic whites.

And for lymphoma, the hazard ratio was 1.28 for Hispanic whites and 1.07 for non-Hispanic blacks compared with the control group.

Colton points to 3 possible reasons for the disparity—residual socioeconomic factors that could influence a patient’s diagnosis and/or care, the possibility for genetically distinct forms of the diseases to make cancers more dangerous in certain populations, or the medical system fails to offer equal diagnosis and treatment across racial/ethnic groups.

The researchers presented these findings as abstract 6557. They recommend further exploration to determine the mechanisms of these disparities.

Poster session at ASCO 2016

© ASCO/Zach Boyden-Holmes

CHICAGO—Hispanic white and non-Hispanic black adolescents and young adults (AYA) are more likely to die of their disease than the same-aged white patients, according to a study presented at the 2016 ASCO Annual Meeting.

If the chance of a young-adult white patient dying within 2 years of receiving a liver cancer diagnosis is a baseline of 1, the chance of a similar Hispanic white patient dying is 1.77 and a non-Hispanic black patient's chance of dying is 1.76.

And this holds true across cancer types, including germ cell tumors, soft tissue sarcomas, lymphomas, and leukemias.

"What this means is that black and Hispanic young adult patients are almost 75% more likely to die after being diagnosed with liver cancer than are white young adult patients," said co-investigator Meryl Colton, a medical student at the University of Colorado.

Using data from the Surveillance, Epidemiologic and End Results (SEER) database, Colton and Adam L. Green, MD, of Children’s Hospital Colorado in Aurora, compared adolescents and young adults between the ages of 15 and 29 to evaluate racial/ethnic disparities in this age population, which is at particular risk for disparities in socioeconomic status and delayed diagnosis.

Even after controlling for insurance status and stage at diagnosis, the researchers determined that there were disparities in death rates for Hispanic whites, non-Hispanic blacks, and Hispanic blacks.

This implies that there is an influence of race/ethnicity independent of financial resources.

For leukemia, the hazard ratio was 1.15 for Hispanic whites and 1.05 for non-Hispanic blacks compared with non-Hispanic whites.

And for lymphoma, the hazard ratio was 1.28 for Hispanic whites and 1.07 for non-Hispanic blacks compared with the control group.

Colton points to 3 possible reasons for the disparity—residual socioeconomic factors that could influence a patient’s diagnosis and/or care, the possibility for genetically distinct forms of the diseases to make cancers more dangerous in certain populations, or the medical system fails to offer equal diagnosis and treatment across racial/ethnic groups.

The researchers presented these findings as abstract 6557. They recommend further exploration to determine the mechanisms of these disparities.

Poster session at ASCO 2016

© ASCO/Zach Boyden-Holmes

CHICAGO—Hispanic white and non-Hispanic black adolescents and young adults (AYA) are more likely to die of their disease than the same-aged white patients, according to a study presented at the 2016 ASCO Annual Meeting.

If the chance of a young-adult white patient dying within 2 years of receiving a liver cancer diagnosis is a baseline of 1, the chance of a similar Hispanic white patient dying is 1.77 and a non-Hispanic black patient's chance of dying is 1.76.

And this holds true across cancer types, including germ cell tumors, soft tissue sarcomas, lymphomas, and leukemias.

"What this means is that black and Hispanic young adult patients are almost 75% more likely to die after being diagnosed with liver cancer than are white young adult patients," said co-investigator Meryl Colton, a medical student at the University of Colorado.

Using data from the Surveillance, Epidemiologic and End Results (SEER) database, Colton and Adam L. Green, MD, of Children’s Hospital Colorado in Aurora, compared adolescents and young adults between the ages of 15 and 29 to evaluate racial/ethnic disparities in this age population, which is at particular risk for disparities in socioeconomic status and delayed diagnosis.

Even after controlling for insurance status and stage at diagnosis, the researchers determined that there were disparities in death rates for Hispanic whites, non-Hispanic blacks, and Hispanic blacks.

This implies that there is an influence of race/ethnicity independent of financial resources.

For leukemia, the hazard ratio was 1.15 for Hispanic whites and 1.05 for non-Hispanic blacks compared with non-Hispanic whites.

And for lymphoma, the hazard ratio was 1.28 for Hispanic whites and 1.07 for non-Hispanic blacks compared with the control group.

Colton points to 3 possible reasons for the disparity—residual socioeconomic factors that could influence a patient’s diagnosis and/or care, the possibility for genetically distinct forms of the diseases to make cancers more dangerous in certain populations, or the medical system fails to offer equal diagnosis and treatment across racial/ethnic groups.

The researchers presented these findings as abstract 6557. They recommend further exploration to determine the mechanisms of these disparities.