A couple made a baby boy. Into him they poured their hopes and dreams. But life is strange with its twists and turns, and things rarely go as planned.

The baby had a rough start. His brain was severely injured. The parents were told the chances of meaningful recovery were close to nothing. With heavy hearts but their son’s best interest in mind, they made the hardest decision of their lives – to provide for his comfort and nothing more. His life supports withdrawn, he was handed to them.

He did not die. Instead, he breathed. With that singular, definitive act, he proved his presence to them. They took him home, unsure what would come next. They did what anyone faced with such terrifying circumstances would have done – they fell in love with their baby. Their goals changed, but their love did not. Tinted by love, his staring spells became looks of cognizance, his reflexes became volitional motions. Think what you may, but do not judge them.

Unexpectedly, he has reached the age of 15 months. Through it all, the mother and father have been the perfect parents of a complex patient. But now he refuses to play the role of stable complex child. Instead, he is steadily worsening. It is easy for me to see this as I take ICU calls every fourth night. Not so for them. I don’t know what it feels like to build a dream and watch it crumble like sand, then to have to learn to carry on with what is left. I cannot imagine living a moment of their lives. Yet there they sit, next to him, waiting for rounds with smiling faces.

We are stuck. We wonder what’s in his best interest – to intervene with an invasive procedure that may allow him to go home or to withdraw interventions and provide him with comfort.

In my eyes, the real question is – where does he live? His parents believe that he is in the body lying on the bed. I can see why they feel this way – if he isn’t there, then what has any of this meant? Has he never been there? Did he leave sometime between defying death and creeping back toward it? These are frightening thoughts to face, indeed. And so, thoroughly entrenched, they must press on lest it be felt that they gave up on him.

I don’t know where he lives. Somewhere else? Heaven perhaps. In his parent’s memories for certain, and in my thoughts as well. In this limp body on the bed? I’m not so sure. But as he stares into his mother’s eyes, and jerks in response to her voice, I begin to doubt myself. How can I help them make this decision?

Perhaps this is the final lesson that residency will teach me.

No. I suspect I still won’t have an answer for the next parents I meet, once his story has played out. Only more questions. …

Dr. Behere was a pediatric resident at the Children’s Hospital at Dartmouth-Hitchcock, Lebanon, N.H., when he wrote this article. He is a first-year fellow in pediatric cardiology at the Nemours Cardiac Center at the Nemours/Alfred I. duPont Hospital for Children, Wilmington, Del. E-mail him at [email protected].

A couple made a baby boy. Into him they poured their hopes and dreams. But life is strange with its twists and turns, and things rarely go as planned.

The baby had a rough start. His brain was severely injured. The parents were told the chances of meaningful recovery were close to nothing. With heavy hearts but their son’s best interest in mind, they made the hardest decision of their lives – to provide for his comfort and nothing more. His life supports withdrawn, he was handed to them.

He did not die. Instead, he breathed. With that singular, definitive act, he proved his presence to them. They took him home, unsure what would come next. They did what anyone faced with such terrifying circumstances would have done – they fell in love with their baby. Their goals changed, but their love did not. Tinted by love, his staring spells became looks of cognizance, his reflexes became volitional motions. Think what you may, but do not judge them.

Unexpectedly, he has reached the age of 15 months. Through it all, the mother and father have been the perfect parents of a complex patient. But now he refuses to play the role of stable complex child. Instead, he is steadily worsening. It is easy for me to see this as I take ICU calls every fourth night. Not so for them. I don’t know what it feels like to build a dream and watch it crumble like sand, then to have to learn to carry on with what is left. I cannot imagine living a moment of their lives. Yet there they sit, next to him, waiting for rounds with smiling faces.

We are stuck. We wonder what’s in his best interest – to intervene with an invasive procedure that may allow him to go home or to withdraw interventions and provide him with comfort.

In my eyes, the real question is – where does he live? His parents believe that he is in the body lying on the bed. I can see why they feel this way – if he isn’t there, then what has any of this meant? Has he never been there? Did he leave sometime between defying death and creeping back toward it? These are frightening thoughts to face, indeed. And so, thoroughly entrenched, they must press on lest it be felt that they gave up on him.

I don’t know where he lives. Somewhere else? Heaven perhaps. In his parent’s memories for certain, and in my thoughts as well. In this limp body on the bed? I’m not so sure. But as he stares into his mother’s eyes, and jerks in response to her voice, I begin to doubt myself. How can I help them make this decision?

Perhaps this is the final lesson that residency will teach me.

No. I suspect I still won’t have an answer for the next parents I meet, once his story has played out. Only more questions. …

Dr. Behere was a pediatric resident at the Children’s Hospital at Dartmouth-Hitchcock, Lebanon, N.H., when he wrote this article. He is a first-year fellow in pediatric cardiology at the Nemours Cardiac Center at the Nemours/Alfred I. duPont Hospital for Children, Wilmington, Del. E-mail him at [email protected].

A couple made a baby boy. Into him they poured their hopes and dreams. But life is strange with its twists and turns, and things rarely go as planned.

The baby had a rough start. His brain was severely injured. The parents were told the chances of meaningful recovery were close to nothing. With heavy hearts but their son’s best interest in mind, they made the hardest decision of their lives – to provide for his comfort and nothing more. His life supports withdrawn, he was handed to them.

He did not die. Instead, he breathed. With that singular, definitive act, he proved his presence to them. They took him home, unsure what would come next. They did what anyone faced with such terrifying circumstances would have done – they fell in love with their baby. Their goals changed, but their love did not. Tinted by love, his staring spells became looks of cognizance, his reflexes became volitional motions. Think what you may, but do not judge them.

Unexpectedly, he has reached the age of 15 months. Through it all, the mother and father have been the perfect parents of a complex patient. But now he refuses to play the role of stable complex child. Instead, he is steadily worsening. It is easy for me to see this as I take ICU calls every fourth night. Not so for them. I don’t know what it feels like to build a dream and watch it crumble like sand, then to have to learn to carry on with what is left. I cannot imagine living a moment of their lives. Yet there they sit, next to him, waiting for rounds with smiling faces.

We are stuck. We wonder what’s in his best interest – to intervene with an invasive procedure that may allow him to go home or to withdraw interventions and provide him with comfort.

In my eyes, the real question is – where does he live? His parents believe that he is in the body lying on the bed. I can see why they feel this way – if he isn’t there, then what has any of this meant? Has he never been there? Did he leave sometime between defying death and creeping back toward it? These are frightening thoughts to face, indeed. And so, thoroughly entrenched, they must press on lest it be felt that they gave up on him.

I don’t know where he lives. Somewhere else? Heaven perhaps. In his parent’s memories for certain, and in my thoughts as well. In this limp body on the bed? I’m not so sure. But as he stares into his mother’s eyes, and jerks in response to her voice, I begin to doubt myself. How can I help them make this decision?

Perhaps this is the final lesson that residency will teach me.

No. I suspect I still won’t have an answer for the next parents I meet, once his story has played out. Only more questions. …

Dr. Behere was a pediatric resident at the Children’s Hospital at Dartmouth-Hitchcock, Lebanon, N.H., when he wrote this article. He is a first-year fellow in pediatric cardiology at the Nemours Cardiac Center at the Nemours/Alfred I. duPont Hospital for Children, Wilmington, Del. E-mail him at [email protected].

Background Patients undergoing chemoradiation for head and neck squamous cell carcinoma (HNSCC) are predisposed to unplanned hospitalizations.

Objective To assess the factors associated with prolonged hospitalization and its impact on patient outcomes.

Methods We assessed the outcomes of patients hospitalized for ≥5 days or <5 days in 251 patients with advanced HNSCC who were undergoing radiotherapy during 2000-2012.

Results Patients who had been hospitalized for ≥5 days were more likely to be admitted for infection, acute renal failure, and/ or dehydration. We found no other patient, tumor, or treatment characteristics associated with prolonged hospitalizations. Hospitalizations of ≥5 days were associated with a higher incidence of delays in radiotherapy (RT; odds ratio [OR], 2.49; 95% confidence index [CI], 1.09-5.69; P = .03) and worse performance status after RT (OR, 5.76; 95% CI, 1.85-18.38; P = .003). On multivariate analysis, hospitalization of ≥5 days predicted for worse local-regional control (hazard ratio [HR], 1.85; 95% CI, 1.08-3.17; P = .03) and time to treatment failure (HR, 1.64; 95% CI, 1.03-2.61; P = .04), and performance status after RT predicted for worse local-regional control, time to treatment failure, progression-free survival, and overall survival.

Limitations As a retrospective review, we report only hypothesis-generating observations, which may have been affected by having incomplete patient information.

Conclusions Hospitalizations of ≥5 days was associated with infections and/or dehydration and predicted for worse disease control. Our results suggest that patients may benefit from efforts to reduce hospitalization length by minimizing precipitators of hospitalizations as well as interventions to reduce the length of hospital stays.

Click on the PDF icon at the top of this introduction to read the full article.

Background Patients undergoing chemoradiation for head and neck squamous cell carcinoma (HNSCC) are predisposed to unplanned hospitalizations.

Objective To assess the factors associated with prolonged hospitalization and its impact on patient outcomes.

Methods We assessed the outcomes of patients hospitalized for ≥5 days or <5 days in 251 patients with advanced HNSCC who were undergoing radiotherapy during 2000-2012.

Results Patients who had been hospitalized for ≥5 days were more likely to be admitted for infection, acute renal failure, and/ or dehydration. We found no other patient, tumor, or treatment characteristics associated with prolonged hospitalizations. Hospitalizations of ≥5 days were associated with a higher incidence of delays in radiotherapy (RT; odds ratio [OR], 2.49; 95% confidence index [CI], 1.09-5.69; P = .03) and worse performance status after RT (OR, 5.76; 95% CI, 1.85-18.38; P = .003). On multivariate analysis, hospitalization of ≥5 days predicted for worse local-regional control (hazard ratio [HR], 1.85; 95% CI, 1.08-3.17; P = .03) and time to treatment failure (HR, 1.64; 95% CI, 1.03-2.61; P = .04), and performance status after RT predicted for worse local-regional control, time to treatment failure, progression-free survival, and overall survival.

Limitations As a retrospective review, we report only hypothesis-generating observations, which may have been affected by having incomplete patient information.

Conclusions Hospitalizations of ≥5 days was associated with infections and/or dehydration and predicted for worse disease control. Our results suggest that patients may benefit from efforts to reduce hospitalization length by minimizing precipitators of hospitalizations as well as interventions to reduce the length of hospital stays.

Click on the PDF icon at the top of this introduction to read the full article.

Background Patients undergoing chemoradiation for head and neck squamous cell carcinoma (HNSCC) are predisposed to unplanned hospitalizations.

Objective To assess the factors associated with prolonged hospitalization and its impact on patient outcomes.

Methods We assessed the outcomes of patients hospitalized for ≥5 days or <5 days in 251 patients with advanced HNSCC who were undergoing radiotherapy during 2000-2012.

Results Patients who had been hospitalized for ≥5 days were more likely to be admitted for infection, acute renal failure, and/ or dehydration. We found no other patient, tumor, or treatment characteristics associated with prolonged hospitalizations. Hospitalizations of ≥5 days were associated with a higher incidence of delays in radiotherapy (RT; odds ratio [OR], 2.49; 95% confidence index [CI], 1.09-5.69; P = .03) and worse performance status after RT (OR, 5.76; 95% CI, 1.85-18.38; P = .003). On multivariate analysis, hospitalization of ≥5 days predicted for worse local-regional control (hazard ratio [HR], 1.85; 95% CI, 1.08-3.17; P = .03) and time to treatment failure (HR, 1.64; 95% CI, 1.03-2.61; P = .04), and performance status after RT predicted for worse local-regional control, time to treatment failure, progression-free survival, and overall survival.

Limitations As a retrospective review, we report only hypothesis-generating observations, which may have been affected by having incomplete patient information.

Conclusions Hospitalizations of ≥5 days was associated with infections and/or dehydration and predicted for worse disease control. Our results suggest that patients may benefit from efforts to reduce hospitalization length by minimizing precipitators of hospitalizations as well as interventions to reduce the length of hospital stays.

Click on the PDF icon at the top of this introduction to read the full article.

Background Community oncologists need a simplified methodology for assessing the value of anticancer drugs. In the United States and Europe, costs of anticancer drug were previously estimated at US$50,000 to >US$100,000 per quality-adjusted life-year (QALY). The National Institute for Health and Care Excellence in the United Kingdom states that the average cost-effectiveness ratios intervention of >US$50,000 per QALY must be questioned.

Objectives To design a drug model to estimate the amount in United States dollars (US$) paid for life-year gain (LYG) and QALY, and to apply that model in the treatment of chemo-naïve and chemo-treated patients with castrate-resistant metastatic prostate cancer (mCRPC).

Methods Cost per LYG (cost/LYG) was compared with cost per probability of survival (cost/PoS) calculated as [1.0 minus HR]. Results were expressed in relative values (RV) calculated as US$50,000 or US$100,000 per cost/outcome.

Results In patients with mCRPC, generic docetaxel demonstrated the lowest cost/LYG (US$26,330), lowest cost/ PoS (US$21,942), and the highest RV (3.80-4.56). Cost/LYG of sipuleucel-T was US$272,195, with an RV of 0.37. Significant variation between cost/LYG and cost/ PoS was noted among drugs with borderline survival and HR. In previously treated patients, the cost/LYG of cabazitaxel was US$207,240; of abiraterone, US$194,087; enzalutamide, US$223,500; and radium-223 dichloride, US$230,000, all with RVs <0.5.

Conclusions A simplified drug model to weigh cost, survival, and HR with imposed limits on cost/outcome was proposed and applied to patients with mCRPC. The results among that patient population suggested that generic docetaxel had the lowest costs, cost/outcome and the highest RV. Sipuleucel-T, abiraterone, enzalutamide, radium-223 dichloride, and cabazitaxel were overpriced for their values. Drugs with RVs of <0.5 should be scrutinized, costs negotiated, or other drugs considered, and those with RVs of <0.25, rejected.

Click on the PDF icon at the top of this introduction to read the full article.

Background Community oncologists need a simplified methodology for assessing the value of anticancer drugs. In the United States and Europe, costs of anticancer drug were previously estimated at US$50,000 to >US$100,000 per quality-adjusted life-year (QALY). The National Institute for Health and Care Excellence in the United Kingdom states that the average cost-effectiveness ratios intervention of >US$50,000 per QALY must be questioned.

Objectives To design a drug model to estimate the amount in United States dollars (US$) paid for life-year gain (LYG) and QALY, and to apply that model in the treatment of chemo-naïve and chemo-treated patients with castrate-resistant metastatic prostate cancer (mCRPC).

Methods Cost per LYG (cost/LYG) was compared with cost per probability of survival (cost/PoS) calculated as [1.0 minus HR]. Results were expressed in relative values (RV) calculated as US$50,000 or US$100,000 per cost/outcome.

Results In patients with mCRPC, generic docetaxel demonstrated the lowest cost/LYG (US$26,330), lowest cost/ PoS (US$21,942), and the highest RV (3.80-4.56). Cost/LYG of sipuleucel-T was US$272,195, with an RV of 0.37. Significant variation between cost/LYG and cost/ PoS was noted among drugs with borderline survival and HR. In previously treated patients, the cost/LYG of cabazitaxel was US$207,240; of abiraterone, US$194,087; enzalutamide, US$223,500; and radium-223 dichloride, US$230,000, all with RVs <0.5.

Conclusions A simplified drug model to weigh cost, survival, and HR with imposed limits on cost/outcome was proposed and applied to patients with mCRPC. The results among that patient population suggested that generic docetaxel had the lowest costs, cost/outcome and the highest RV. Sipuleucel-T, abiraterone, enzalutamide, radium-223 dichloride, and cabazitaxel were overpriced for their values. Drugs with RVs of <0.5 should be scrutinized, costs negotiated, or other drugs considered, and those with RVs of <0.25, rejected.

Click on the PDF icon at the top of this introduction to read the full article.

Background Community oncologists need a simplified methodology for assessing the value of anticancer drugs. In the United States and Europe, costs of anticancer drug were previously estimated at US$50,000 to >US$100,000 per quality-adjusted life-year (QALY). The National Institute for Health and Care Excellence in the United Kingdom states that the average cost-effectiveness ratios intervention of >US$50,000 per QALY must be questioned.

Objectives To design a drug model to estimate the amount in United States dollars (US$) paid for life-year gain (LYG) and QALY, and to apply that model in the treatment of chemo-naïve and chemo-treated patients with castrate-resistant metastatic prostate cancer (mCRPC).

Methods Cost per LYG (cost/LYG) was compared with cost per probability of survival (cost/PoS) calculated as [1.0 minus HR]. Results were expressed in relative values (RV) calculated as US$50,000 or US$100,000 per cost/outcome.

Results In patients with mCRPC, generic docetaxel demonstrated the lowest cost/LYG (US$26,330), lowest cost/ PoS (US$21,942), and the highest RV (3.80-4.56). Cost/LYG of sipuleucel-T was US$272,195, with an RV of 0.37. Significant variation between cost/LYG and cost/ PoS was noted among drugs with borderline survival and HR. In previously treated patients, the cost/LYG of cabazitaxel was US$207,240; of abiraterone, US$194,087; enzalutamide, US$223,500; and radium-223 dichloride, US$230,000, all with RVs <0.5.

Conclusions A simplified drug model to weigh cost, survival, and HR with imposed limits on cost/outcome was proposed and applied to patients with mCRPC. The results among that patient population suggested that generic docetaxel had the lowest costs, cost/outcome and the highest RV. Sipuleucel-T, abiraterone, enzalutamide, radium-223 dichloride, and cabazitaxel were overpriced for their values. Drugs with RVs of <0.5 should be scrutinized, costs negotiated, or other drugs considered, and those with RVs of <0.25, rejected.

Click on the PDF icon at the top of this introduction to read the full article.

Uncontrolled pain is one of the most feared and debilitating symptoms among cancer patients, and many suffer unnecessarily from suboptimal pain control. Cancer-related pain is often multidimensional and can affect all aspects of a patient’s life. Hence, achieving adequate pain relief among cancer patients involves a proper assessment of psychosocial, spiritual, and physical pain issues, matched with an individualized treatment plan involving pharmacologic, nonpharmacologic, and procedural therapies when appropriate. Providing effective pain relief can help ease the overall burden of disease among oncology patients while helping them tolerate cancer-directed therapies and achieve the most optimal quality of life throughout all phases of the disease continuum. In this review, the authors will discuss the syndromes, assessment of, and treatment for cancer-related pain in the outpatient setting.

Click on the PDF icon at the top of this introduction to read the full article.

Uncontrolled pain is one of the most feared and debilitating symptoms among cancer patients, and many suffer unnecessarily from suboptimal pain control. Cancer-related pain is often multidimensional and can affect all aspects of a patient’s life. Hence, achieving adequate pain relief among cancer patients involves a proper assessment of psychosocial, spiritual, and physical pain issues, matched with an individualized treatment plan involving pharmacologic, nonpharmacologic, and procedural therapies when appropriate. Providing effective pain relief can help ease the overall burden of disease among oncology patients while helping them tolerate cancer-directed therapies and achieve the most optimal quality of life throughout all phases of the disease continuum. In this review, the authors will discuss the syndromes, assessment of, and treatment for cancer-related pain in the outpatient setting.

Click on the PDF icon at the top of this introduction to read the full article.

Uncontrolled pain is one of the most feared and debilitating symptoms among cancer patients, and many suffer unnecessarily from suboptimal pain control. Cancer-related pain is often multidimensional and can affect all aspects of a patient’s life. Hence, achieving adequate pain relief among cancer patients involves a proper assessment of psychosocial, spiritual, and physical pain issues, matched with an individualized treatment plan involving pharmacologic, nonpharmacologic, and procedural therapies when appropriate. Providing effective pain relief can help ease the overall burden of disease among oncology patients while helping them tolerate cancer-directed therapies and achieve the most optimal quality of life throughout all phases of the disease continuum. In this review, the authors will discuss the syndromes, assessment of, and treatment for cancer-related pain in the outpatient setting.

Click on the PDF icon at the top of this introduction to read the full article.

SEATTLE – Targeted therapies for melanoma are improving outcomes for patients with brain metastases and changing management of this dreaded complication, according to Dr. John A. Thompson, codirector of the Melanoma Clinic at the Seattle Cancer Care Alliance and a professor in the medical oncology division at the University of Washington, both in Seattle.

“We are in a new era of treatment of brain metastasis. It’s no longer just surgery and radiation therapy, but a multidisciplinary approach involving medical oncology, radiation oncology, and surgery,” he told attendees of the World Cutaneous Malignancies Congress.

Without question, surgery and radiation therapy techniques have advanced over time, and these modalities remain helpful in achieving local control of disease. Additionally, greater experience with them has improved patient selection.

For example, research has identified several predictors of benefit from stereotactic radiosurgery, such as fewer brain metastases and better performance status (J Neurosurg. 2011;114:769-79). But overall survival was fairly poor given disease elsewhere in the body. “Here’s where I think the new developments in systemic therapy may hopefully be able to start improving this curve,” Dr. Thompson said.

Toxicity of some forms of radiation therapy also remains problematic. For example, a recent randomized phase III trial in patients with up to three brain metastases showed that addition of whole-brain radiation therapy to radiosurgery improved intracranial tumor control, but at the expense of more rapid cognitive decline (ASCO 2015. Abstract LBA4). And there was no gain in overall survival.

“The changes that have happened in systemic therapy over the past 5-10 years have been very exciting,” Dr. Thompson said. By way of example, he pointed to a phase II trial that tested ipilimumab (Yervoy), an antibody to the T-cell receptor cytotoxic T lymphocyte–associated antigen 4 (CTLA4), as induction therapy and then maintenance therapy among patients with melanoma who had brain metastases (Lancet Oncol. 2012;13:459-65).

The subset of patients who were neurologically stable and not on systemic steroids had a disease control rate of 24%, with some having objective responses, including ones in the CNS; the value was lower, at 10%, among patients who were neurologically symptomatic and on steroids, indicating more advanced disease. The 2-year overall survival rate was 26%.

“I think this is encouraging if you compare [these patients] to historical control patients with brain metastases,” said Dr. Thompson, who disclosed that he performs contracted research with Agensys, BMS, Merck, Novartis, and Pfizer.

Another phase II trial, CheckMate 204, which is currently enrolling patients, is taking the concept further, testing the combination of ipilimumab and nivolumab (Opdivo), an antibody to the cell surface receptor programmed death-1 (PD-1), as induction therapy followed by nivolumab maintenance therapy among patients with melanoma who have brain metastases. “This is I think a high-priority trial,” he asserted.

Discussing some cases from his own practice, Dr. Thompson described patient-tailored integration of the new systemic therapies with surgery and radiation therapy.

Oncologists must often deal with toxicities of these therapies as well, such as the colitis and hypophysitis related to ipilimumab therapy, and the development of resistance over time, Dr. Thompson acknowledged.

Nonetheless, the multimodality approach has led to regression and elimination of brain metastases, and even allowed some patients to achieve remission, he reported.

SEATTLE – Targeted therapies for melanoma are improving outcomes for patients with brain metastases and changing management of this dreaded complication, according to Dr. John A. Thompson, codirector of the Melanoma Clinic at the Seattle Cancer Care Alliance and a professor in the medical oncology division at the University of Washington, both in Seattle.

“We are in a new era of treatment of brain metastasis. It’s no longer just surgery and radiation therapy, but a multidisciplinary approach involving medical oncology, radiation oncology, and surgery,” he told attendees of the World Cutaneous Malignancies Congress.

Without question, surgery and radiation therapy techniques have advanced over time, and these modalities remain helpful in achieving local control of disease. Additionally, greater experience with them has improved patient selection.

For example, research has identified several predictors of benefit from stereotactic radiosurgery, such as fewer brain metastases and better performance status (J Neurosurg. 2011;114:769-79). But overall survival was fairly poor given disease elsewhere in the body. “Here’s where I think the new developments in systemic therapy may hopefully be able to start improving this curve,” Dr. Thompson said.

Toxicity of some forms of radiation therapy also remains problematic. For example, a recent randomized phase III trial in patients with up to three brain metastases showed that addition of whole-brain radiation therapy to radiosurgery improved intracranial tumor control, but at the expense of more rapid cognitive decline (ASCO 2015. Abstract LBA4). And there was no gain in overall survival.

“The changes that have happened in systemic therapy over the past 5-10 years have been very exciting,” Dr. Thompson said. By way of example, he pointed to a phase II trial that tested ipilimumab (Yervoy), an antibody to the T-cell receptor cytotoxic T lymphocyte–associated antigen 4 (CTLA4), as induction therapy and then maintenance therapy among patients with melanoma who had brain metastases (Lancet Oncol. 2012;13:459-65).

The subset of patients who were neurologically stable and not on systemic steroids had a disease control rate of 24%, with some having objective responses, including ones in the CNS; the value was lower, at 10%, among patients who were neurologically symptomatic and on steroids, indicating more advanced disease. The 2-year overall survival rate was 26%.

“I think this is encouraging if you compare [these patients] to historical control patients with brain metastases,” said Dr. Thompson, who disclosed that he performs contracted research with Agensys, BMS, Merck, Novartis, and Pfizer.

Another phase II trial, CheckMate 204, which is currently enrolling patients, is taking the concept further, testing the combination of ipilimumab and nivolumab (Opdivo), an antibody to the cell surface receptor programmed death-1 (PD-1), as induction therapy followed by nivolumab maintenance therapy among patients with melanoma who have brain metastases. “This is I think a high-priority trial,” he asserted.

Discussing some cases from his own practice, Dr. Thompson described patient-tailored integration of the new systemic therapies with surgery and radiation therapy.

Oncologists must often deal with toxicities of these therapies as well, such as the colitis and hypophysitis related to ipilimumab therapy, and the development of resistance over time, Dr. Thompson acknowledged.

Nonetheless, the multimodality approach has led to regression and elimination of brain metastases, and even allowed some patients to achieve remission, he reported.

SEATTLE – Targeted therapies for melanoma are improving outcomes for patients with brain metastases and changing management of this dreaded complication, according to Dr. John A. Thompson, codirector of the Melanoma Clinic at the Seattle Cancer Care Alliance and a professor in the medical oncology division at the University of Washington, both in Seattle.

“We are in a new era of treatment of brain metastasis. It’s no longer just surgery and radiation therapy, but a multidisciplinary approach involving medical oncology, radiation oncology, and surgery,” he told attendees of the World Cutaneous Malignancies Congress.

Without question, surgery and radiation therapy techniques have advanced over time, and these modalities remain helpful in achieving local control of disease. Additionally, greater experience with them has improved patient selection.

For example, research has identified several predictors of benefit from stereotactic radiosurgery, such as fewer brain metastases and better performance status (J Neurosurg. 2011;114:769-79). But overall survival was fairly poor given disease elsewhere in the body. “Here’s where I think the new developments in systemic therapy may hopefully be able to start improving this curve,” Dr. Thompson said.

Toxicity of some forms of radiation therapy also remains problematic. For example, a recent randomized phase III trial in patients with up to three brain metastases showed that addition of whole-brain radiation therapy to radiosurgery improved intracranial tumor control, but at the expense of more rapid cognitive decline (ASCO 2015. Abstract LBA4). And there was no gain in overall survival.

“The changes that have happened in systemic therapy over the past 5-10 years have been very exciting,” Dr. Thompson said. By way of example, he pointed to a phase II trial that tested ipilimumab (Yervoy), an antibody to the T-cell receptor cytotoxic T lymphocyte–associated antigen 4 (CTLA4), as induction therapy and then maintenance therapy among patients with melanoma who had brain metastases (Lancet Oncol. 2012;13:459-65).

The subset of patients who were neurologically stable and not on systemic steroids had a disease control rate of 24%, with some having objective responses, including ones in the CNS; the value was lower, at 10%, among patients who were neurologically symptomatic and on steroids, indicating more advanced disease. The 2-year overall survival rate was 26%.

“I think this is encouraging if you compare [these patients] to historical control patients with brain metastases,” said Dr. Thompson, who disclosed that he performs contracted research with Agensys, BMS, Merck, Novartis, and Pfizer.

Another phase II trial, CheckMate 204, which is currently enrolling patients, is taking the concept further, testing the combination of ipilimumab and nivolumab (Opdivo), an antibody to the cell surface receptor programmed death-1 (PD-1), as induction therapy followed by nivolumab maintenance therapy among patients with melanoma who have brain metastases. “This is I think a high-priority trial,” he asserted.

Discussing some cases from his own practice, Dr. Thompson described patient-tailored integration of the new systemic therapies with surgery and radiation therapy.

Oncologists must often deal with toxicities of these therapies as well, such as the colitis and hypophysitis related to ipilimumab therapy, and the development of resistance over time, Dr. Thompson acknowledged.

Nonetheless, the multimodality approach has led to regression and elimination of brain metastases, and even allowed some patients to achieve remission, he reported.

Serum concentration of hyaluronic acid correlated with the severity of knee osteoarthritis in a longitudinal population-based cohort, with concentrations above 51.9 ng/mL significantly associated with progression in people with moderate disease.

While previous studies have suggested cutoff values for serum hyaluronic acid (HA) as biomarkers for progression of knee osteoarthritis, this study, conducted by Dr. Eiji Sasaki of Hirosaki (Japan) University and his colleagues, is the first to report a serum HA cutoff value from a longitudinal study.

©decade3d/Thinkstock.com

The investigators prospectively enrolled 720 volunteers into a community-based preventive medicine program with intent to follow them for 5 years. They excluded patients with renal failure, liver failure, rheumatoid arthritis, or cancer, as all of these can increase serum HA. HA concentrations and knee radiography were taken at baseline and at 5-year follow-up, with complete data from 444 patients (mean age 55, 64% female) entered into analysis. Dr. Sasaki and his colleagues measured severity of knee osteoarthritis using Kellgren-Lawrence grades. Higher serum HA at baseline correlated with KL grade progression in the cohort as a whole (P = .004), and HA concentration was linked to joint space narrowing in knees with no disease or mild disease (KL grades 0-1) and moderate disease (KL grades 2 or 3) at baseline (P = .021 and P = .008, respectively).

Serum HA of 51.9 ng/mL was predictive of knee osteoarthritis progression in subjects (n = 119) with KL grades 2 or 3 disease (area under curve [AUC], 0.707), and associated with a fivefold increase (odds ratio, 4.89) in risk of joint space narrowing over 5 years. For people with mild or no disease at baseline (n = 323), Dr. Sasaki and his colleagues identified a cutoff of 35.1 ng/mL for the development of OA, but it was not a robust indicator with an AUC of 0.603 (Arthritis Res Ther. 2015;17:283. doi: 10.1186/s13075-015-0793-0).

“Further clinical studies are needed to determine whether serum HA can predict the incidence of OA, which was not determined in the present study,” Dr. Sasaki and his colleagues wrote in their analysis. They noted that the cutoff value of 51.9 ng/mL “should be useful during screening for abnormal knee conditions or as an additional evaluation for the risk of OA progression when used in combination with conventional imaging tools.”

The study was funded by grants from the Japanese government, the Japanese Society for the Promotion of Science, and the Japanese Orthopedic Association. Dr. Sasaki and colleagues declared no conflicts of interest.

Serum concentration of hyaluronic acid correlated with the severity of knee osteoarthritis in a longitudinal population-based cohort, with concentrations above 51.9 ng/mL significantly associated with progression in people with moderate disease.

While previous studies have suggested cutoff values for serum hyaluronic acid (HA) as biomarkers for progression of knee osteoarthritis, this study, conducted by Dr. Eiji Sasaki of Hirosaki (Japan) University and his colleagues, is the first to report a serum HA cutoff value from a longitudinal study.

©decade3d/Thinkstock.com

The investigators prospectively enrolled 720 volunteers into a community-based preventive medicine program with intent to follow them for 5 years. They excluded patients with renal failure, liver failure, rheumatoid arthritis, or cancer, as all of these can increase serum HA. HA concentrations and knee radiography were taken at baseline and at 5-year follow-up, with complete data from 444 patients (mean age 55, 64% female) entered into analysis. Dr. Sasaki and his colleagues measured severity of knee osteoarthritis using Kellgren-Lawrence grades. Higher serum HA at baseline correlated with KL grade progression in the cohort as a whole (P = .004), and HA concentration was linked to joint space narrowing in knees with no disease or mild disease (KL grades 0-1) and moderate disease (KL grades 2 or 3) at baseline (P = .021 and P = .008, respectively).

Serum HA of 51.9 ng/mL was predictive of knee osteoarthritis progression in subjects (n = 119) with KL grades 2 or 3 disease (area under curve [AUC], 0.707), and associated with a fivefold increase (odds ratio, 4.89) in risk of joint space narrowing over 5 years. For people with mild or no disease at baseline (n = 323), Dr. Sasaki and his colleagues identified a cutoff of 35.1 ng/mL for the development of OA, but it was not a robust indicator with an AUC of 0.603 (Arthritis Res Ther. 2015;17:283. doi: 10.1186/s13075-015-0793-0).

“Further clinical studies are needed to determine whether serum HA can predict the incidence of OA, which was not determined in the present study,” Dr. Sasaki and his colleagues wrote in their analysis. They noted that the cutoff value of 51.9 ng/mL “should be useful during screening for abnormal knee conditions or as an additional evaluation for the risk of OA progression when used in combination with conventional imaging tools.”

The study was funded by grants from the Japanese government, the Japanese Society for the Promotion of Science, and the Japanese Orthopedic Association. Dr. Sasaki and colleagues declared no conflicts of interest.

Serum concentration of hyaluronic acid correlated with the severity of knee osteoarthritis in a longitudinal population-based cohort, with concentrations above 51.9 ng/mL significantly associated with progression in people with moderate disease.

While previous studies have suggested cutoff values for serum hyaluronic acid (HA) as biomarkers for progression of knee osteoarthritis, this study, conducted by Dr. Eiji Sasaki of Hirosaki (Japan) University and his colleagues, is the first to report a serum HA cutoff value from a longitudinal study.

©decade3d/Thinkstock.com

The investigators prospectively enrolled 720 volunteers into a community-based preventive medicine program with intent to follow them for 5 years. They excluded patients with renal failure, liver failure, rheumatoid arthritis, or cancer, as all of these can increase serum HA. HA concentrations and knee radiography were taken at baseline and at 5-year follow-up, with complete data from 444 patients (mean age 55, 64% female) entered into analysis. Dr. Sasaki and his colleagues measured severity of knee osteoarthritis using Kellgren-Lawrence grades. Higher serum HA at baseline correlated with KL grade progression in the cohort as a whole (P = .004), and HA concentration was linked to joint space narrowing in knees with no disease or mild disease (KL grades 0-1) and moderate disease (KL grades 2 or 3) at baseline (P = .021 and P = .008, respectively).

Serum HA of 51.9 ng/mL was predictive of knee osteoarthritis progression in subjects (n = 119) with KL grades 2 or 3 disease (area under curve [AUC], 0.707), and associated with a fivefold increase (odds ratio, 4.89) in risk of joint space narrowing over 5 years. For people with mild or no disease at baseline (n = 323), Dr. Sasaki and his colleagues identified a cutoff of 35.1 ng/mL for the development of OA, but it was not a robust indicator with an AUC of 0.603 (Arthritis Res Ther. 2015;17:283. doi: 10.1186/s13075-015-0793-0).

“Further clinical studies are needed to determine whether serum HA can predict the incidence of OA, which was not determined in the present study,” Dr. Sasaki and his colleagues wrote in their analysis. They noted that the cutoff value of 51.9 ng/mL “should be useful during screening for abnormal knee conditions or as an additional evaluation for the risk of OA progression when used in combination with conventional imaging tools.”

The study was funded by grants from the Japanese government, the Japanese Society for the Promotion of Science, and the Japanese Orthopedic Association. Dr. Sasaki and colleagues declared no conflicts of interest.

Moderated by: Stephen Ansell, MD, PhD1

Discussants: Craig Moskowitz, MD2; Catherine Diefenbach, MD3; Andrew M. Evens, DO, MSc4

From Mayo Clinic, Rochester, MN¹; Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY²; NYU School of Medicine and NYU Perlmutter Cancer Center, New York, NY³; Tufts University School of Medicine and Tufts Medical Center, Boston, MA⁴

Address for correspondence: Stephen Ansell, MD, PhD, Mayo Clinic, 200 First Street SW #W10, Rochester, MN 55905

E-mail: [email protected]

Biographical sketch:

From Weill Medical College of Cornell University:

Dr. Moskowitz serves as principal investigator and co-investigator for a number of clinical trials aimed at improving the care of patients with lymphoma. His research has focused on improving the outcome of patients with poor-risk diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL). This effort has been conducted along two tracks. One effort is focused on improving therapy for patients with disease that has returned or is not responding to standard therapy (refractory disease), through the use of high-dose therapy and autologous stem cell transplantation as well as new agents that can be incorporated into such "salvage" therapy. The second is aimed at developing risk-adapted strategies to optimize the treatment of newly diagnosed DLBCL by using what we have learned in the relapsed and refractory setting. 

Dr. Moskowitz has been recognized for his research on a national level through multiple awards. He has lectured worldwide on lymphoma and stem cell transplantation. In addition, he is a member of the research council at MSKCC, and on the steering committees for the bi-annual international lymphoma conference in Lugano and international Hodgkin lymphoma conference in Cologne.

From NYU School of Medicine and NYU Perlmutter Cancer Center:

An alumna of the University of Pennsylvania School of Medicine, Dr. Diefenbach completed her internship and residency at the Johns Hopkins Hospital and her oncology fellowship at Memorial Sloan-Kettering Cancer Center, where she spent an additional year focusing on translational immunology.

Her scientific research focuses on the relationship between lymphoma and immunity; on developing novel and immune based treatment strategies for patients with relapsed lymphoma; and on biomarker discovery. She is currently leading a national clinical trial for relapsed Hodgkin lymphoma investigating the combination of the antibody drug conjugate brentuximab with the immune activating agents ipilimumab and nivolumab. 

Dr. Diefenbach directs the lymphoma clinical research within the Hematology/ Oncology Division at the Perlmutter Cancer Center. She is a member of the ECOG Lymphoma Committee, the NCI Lymphoma Steering Committee Clinical Trials Planning Meeting, and the Editorial Board of Clinical Cancer Research. Her research is supported by the Lymphoma Research Foundation, the American Cancer Society and the National Cancer Institute (NCI). 

From Tufts University School of Medicine and Tufts Medical Center:

DR. ANSELL: My name is Stephen Ansell, from Mayo Clinic, Rochester, Minnesota. I’m joined by Drs. Craig Moskowitz, Attending Physician at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Medical College of Cornell University, Catherine Diefenbach, Assistant Professor of Medicine at the NYU School of Medicine and the NYU Perlmutter Cancer Center, and Andy Evens, Professor of Medicine at Tufts University School of Medicine, and Faculty Member at Tufts Medical Center in Boston.

Welcome to all of you and thank you for participating in this medical roundtable discussion. The focus today is going to be on practical management of Hodgkin lymphoma. This is a very experienced group of roundtable participants whom I hope will give us valuable insights into some of the questions relating to managing Hodgkin lymphoma.

Let’s talk about patients with early stage Hodgkin lymphoma and discuss what we feel the standard management might be and how we would use positron emission tomographic (PET) scans to direct therapy. Craig, I’m going to ask you to start. Please discuss what your standard management of early stage Hodgkin lymphoma is and how you use PET scans to direct your treatment.

DR. MOSKOWITZ: I divide Hodgkin lymphoma, early stage, into three groups; favorable early stage, unfavorable early stage without tumor bulk, and stage two disease with tumor bulk. The standard management is well borne out these days from the German Hodgkin Lymphoma Study Group.^1,2 For early stage favorable Hodgkin lymphoma I treat men and women quite differently.

For men with stage IA or IIA, non-bulky disease, I tend to use standard treatment, which is short course combined modality therapy with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and involved-field radiation. I do not use PET imaging in that setting. For women, however, as you know, the median age is young in this patient population. I’ve adopted a RAPID approach for these folks. I give 3 months of chemotherapy and then repeat the PET scan and if the PET scan is negative I stop treatment. If the PET scan is positive, I treat the patient as per that study, which was one more cycle of chemotherapy and radiation. But unfavorable early-stage disease without tumor bulk, once again, the issue is, should patients get chemotherapy alone or should they get combined modality therapy?

If I’m giving combined modality therapy, I do not use PET imaging. If I’m using chemotherapy alone and if this is a patient eligible for a RAPID approach I treat as above. If the patient was not eligible for RAPID because they had stage IIB disease, I usually give full course chemotherapy and I do not use PET imaging.

For patients with bulky stage II disease, I treat based upon the randomized cooperative group study, which is four to six cycles of chemotherapy followed by radiation. I do not use PET imaging in that setting.

DR. ANSELL: Craig, thanks. Andy, do you actually escalate therapy at any time based on PET results, or deescalate therapy? We heard from Craig that he follows some of the RAPID guidelines. Give us your perspective.

DR. EVENS: I think they’re all good questions. In a way, it’s not one size fits all. I think it has to be a very individualized patient-by-patient treatment decision. In other words, I might approach a 19-year-old woman with a bulky mediastinal mass differently than a 45-year-old man with a right cervical lymph node. This is one important point to convey. In terms of PET-adapted, I think it is evolving. The question is, is there any actionable evidence to go on?

In terms of where there are more data, which is in early negativity in terms of PET-2 negativity, there have been a couple publications alluded to—RAPID and the European Organisation for Research and Treatment of Cancer (EORTC)³—and I’m not sure those data changed the opinion if we didn’t have an early negative PET scan. We know, without an early negative PET scan, that patients who do not receive consolidative radiation have a small improvement in progression-free survival (PFS) and no difference in overall survival (OS).

What both of those studies showed is that basically persists. That margin of difference might be a little less—instead of 6%–8% difference in PFS, it might now be 4%–6%, but both studies proved to be not noninferior, so I’m not quite sure that has changed how I treat someone. In other words, an early negative PET scan. For PET positivity, the data are really evolving. I think, before the Lugano meeting this past June I would have said no.

 I just saw a very recent second opinion on a younger patient in her mid-20s who had a bulky mediastinal mass, and then after two cycles was definitely better, but still PET positive, defined as it was a smidge greater than the liver, and the data that emanated from Lugano on early PET positive showed not only a PFS advantage, but a borderline OS, and that, of course, would be a game changer if PET-adapted therapy is pointing toward an OS advantage.

DR. ANSELL: Catherine, what’s your sense of the role of radiation therapy in early stage Hodgkin lymphoma?

DR. DIEFENBACH: As Andy said, the role of PET to stratify early stage patients is evolving. Another study that was reported in Lugano was the Response-adjusted Therapy for Hodgkin Lymphoma (RATHL) study⁴ where it appeared that for patients who had an early PET negative, the bleomycin could be omitted and the patients ended up with a PFS that was equivalent to patients who did not have bleomycin omitted. The decision of combined modality therapy vs standard therapy—I think Andy and Craig put it really well—will have to be individualized to the patient’s situation: specifically, to their age, sex, bulk of disease, and response after early disease assessment.

DR. MOSKOWITZ: That’s why it’s so hard to study this patient population. You have three folks on the phone and we’re all treating patients differently with an individualized approach. It’s almost impossible to come up with a clinical trial that everybody would be comfortable with in this patient population, which is why we have difficulty in writing one, which is disappointing.

DR. ANSELL: Craig, I wanted to circle back to you. The German Hodgkin Lymphoma Study Group has shown that if you omit bleomycin there is a slight decrease in outcome;⁵ however, the RATHL trial would suggest maybe not.⁶ Has that impacted your practice at all? Do you omit bleomycin in your regimens or do you use it standardly?

DR. MOSKOWITZ: Well, RATHL is for advanced stage disease and I’ve already stopped giving bleomycin to patients who are PET negative after 2 months of ABVD based on that approach; but I do not omit bleomycin for an early stage disease based upon the results from the German Hodgkin Lymphoma Study Group. We’re not giving full course chemotherapy in the early stage setting, so I’m willing to give the appropriate number of cycles, at least for now.

DR. ANSELL: Thanks for your perspectives. I think as it was pointed out, there’s a lot of individualization here and we still have an evolving role of PET scanning. Also, there are multiple new agents we’ll begin to talk about later in the program that may impact things further. So, I think this remains an area where it’s quite challenging to determine the optimal approach.

I want to turn our attention to talk about patients with advanced stage disease—predominantly stage III and IV disease. Catherine, how do you treat patients with advanced stage disease? What’s your approach, and as new agents are coming along, agents like brentuximab vedotin, where do you think they fit into your approach?

DR. DIEFENBACH: Just as Craig said, there isn’t really a one-size-fits-all approach to advanced-stage patients either. Just as early-stage patients are divided into at least three groups, we look at advanced-stage patients as a very heterogeneous population. One of the ways we stratify advanced-stage patients is based on what we call their risk score.

Traditionally, we’ve used the Hasenclever risk score—or the International Prognostic Score (IPS)⁷—which looks at seven clinical factors to get a sense of how these advanced-stage patients are going to do in terms of their PFS and OS.⁷ More recently, we have a manuscript where we’re looking in the modern era at using a streamlined score with only three of these factors instead of seven factors⁸ and the group from British Columbia has showed that, while this Hasenclever risk score is still relevant,⁹ it looks in the modern era with modern chemotherapy that it may be less helpful than it previously was, because the patients who did much worse are doing better, so the curves are narrowed.

Nonetheless, biologically and clinically, there’s a big difference between advanced-stage patients who have zero to two risk factors and advanced-stage patients who have five, six, or seven risk factors. The standard of care for treatment for advanced-stage patients both in the US and internationally has been either the chemotherapy regimen of ABVD or the chemotherapy regimen of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP).^10,11 There has been a controversy between those who prefer escalated BEACOPP and those who prefer ABVD. Escalated BEACOPP has a superior PFS to ABVD, which didn’t necessarily translate into an OS benefit, and patients who fail ABVD may be salvaged with stem cell transplant and second line chemotherapy and stem cell transplant.

Patients with escalated BEACOPP also have substantial therapy-related toxicity that patients with ABVD do not have, such as infertility and myelosuppression, higher rates of neutropenic fever, and higher rates of secondary leukemia, so there’s a cost associated with being treated with escalated BEACOPP that’s not associated with ABVD. With both regimens, the cure rate is approximately 75%–80%, so those who favor ABVD—I would consider myself one of them—would argue that you spare a certain number of patients who are salvaged with ABVD and who are cured unnecessary toxicity with the escalated BEACOPP. Those who are in favor of escalated BEACOPP for all patients would probably argue that an increased PFS should translate into an increased OS, and there have in fact been meta-analyses that show improved OS in some older trials with BEACOPP compared to ABVD, but this is a meta-analysis across many different trials.

More recently, brentuximab vedotin—an antibody drug conjugate, against CD30, which is expressed on the Hodgkin Reed-Sternberg (HRS) cell—combined with auristatin—a taxane-like cytotoxic chemotherapy—which acts like a Trojan horse, is delivered to the HRS cell, taken up by the HRS cell and then blows up the HRS cell while sparing, to a large extent, the microenvironment, has been incorporated into upfront therapy with ABVD.

Brentuximab was approved by the Food and Drug Administration (FDA) to treat relapsed Hodgkin lymphoma based on the pivotal study, which had an overall response rate of approximately 75% for relapsed patients.¹² Based on this it was incorporated into upfront therapy. There was a phase I study which I think, Steve, you actually led, which combined ABVD with brentuximab vedotin.¹³ This, however, resulted in excessive pulmonary toxicity secondary to bleomycin, so bleomycin was then omitted. The data were reported at the American Society of Hematology (ASH) meeting and showed a 3-year failure free survival of 96% and OS of 100%, which is extremely impressive in this population. The Phase 3 Frontline Therapy Trial in Patients With Advanced Classical Hodgkin Lymphoma (ECHELON) [NCT01712490] is currently underway and should complete accrual this year.

I think that these data will certainly help to answer the question of whether incorporating brentuximab into the upfront regimen of ABVD can improve both PFS and OS for these patients and perhaps put BEACOPP, finally, to rest.

DR. ANSELL: Andy, do you have a place in your practice where you think escalated BEACOPP has a role?

DR. EVENS: The quick answer is yes, but that sliver of practice is extremely small, and as time is going on, it’s getting smaller. I think in the pre-response adapted era—5 to 10 years ago when BEACOPP was first published—it did show an OS advantage, but many people would argue the comparator or COPP/ABVD arm isn’t equivalent, so to speak, to contemporary ABVD.

I was using it mainly in patients with high IPS—patients who had a five, six, or seven. That, frankly, is not a large percent of the patient population. Now, in the PET-adapted, we don’t quite have that actionable evidence, as much has accumulated quite yet, as early stage disease. Even in the patients now with high IPS, I have to admit, I’m really starting with ABVD in everyone and only considering escalating in patients who have a positive PET scan, which I guess in my practice is somewhat lower than the clinical trial data.

The clinical trial data in advanced-stage disease would say that’s 15%–20% of the patients.¹⁴ I tend to find it’s closer in the 5% range. I think part of that is viewing the PET-adapted part we keep talking about—it can’t be viewed in a vacuum, meaning you shouldn’t review a report. You should sit side-by-side with your radiologist and try to review that scan, and while doing that, have a clear meaning of what defines PET positive and PET negative, because almost every study we talked about has it slightly different. Where’s the cut point? Is it at the liver—meaning a Deauville score of four or five—or is it less in the liver, etc? So, I think those types of things are very important to understand and appreciate when treating the patients.

DR. DIEFENBACH: Andy, I completely agree with you and I also would have a role for BEACOPP in a patient who was not responding to ABVD with interim scans. I also, at that time, if the patient was by PET/computed tomography unequivocally refractory, I would consider clinical trial probably in the same vein as the escalated BEACOPP. So, I agree with Andy that I have a sliver of patients for whom I do consider escalated BEACOPP, but that is a very small sliver.

DR. ANSELL: Craig, what’s your comment about modifications that are happening, even to escalated BEACOPP? The BrECADD regimen is incorporating new agents like brentuximab vedotin.¹⁵ What’s your thinking about that regimen?

DR. MOSKOWITZ: I don’t treat patients off protocol with protocol based treatment, so my familiarity with it is low. Just to digress for one second, I think that I have definitely changed my practice and I would say that I used to give BEACOPP quite a bit for patients with four to seven risk factors, which is about 20% of the patient population. I think, based upon two fairly large studies that will have about 1700 patients on, the RATHL study and the intergroup study in the United States—it’s fairly clear—to me at least—that one can start with ABVD chemotherapy.

Since 80% of the patients have a negative interim PET scan, despite the number of pre-treatment risk factors they have, you’re really limiting the number of patients who get crossed over to a more complicated program, so I’ve been using that approach. I’m very comfortable with it.

The issue of giving brentuximab vedotin with AVD as part of primary therapy is, once again, investigational, and I have many concerns about the cost of that treatment program and it’s applicability worldwide even if the study is positive.

DR. ANSELL: I think that’s a good point. One of the things I find very interesting as we talk about the escalated BEACOPP vs. ABVD comparison is that as brentuximab vedotin has been mixed into those two regimens, it’s almost as if those two regimens are coming toward each other. ABVD is being somewhat escalated in intensity and escalated BEACOPP being modified down. I think at the end of the day, we’re going to come to a combined approach that suits people on both sides of the intensity debate. Cost, however, is going to be an issue to make this an internationally usable regimen, so I think that’s a real challenge.

I want to pick up, Craig, on the point you made about risks of relapse and so on. When and if patients relapse, what do you use in your practice as the optimal salvage regimen? Also, I know you’re a big advocate for your patients to attain a complete remission before going to transplant, would you like to explain why?

DR. MOSKOWITZ: Once again my opinion about this has evolved over the years, but I think that I’m fairly comfortable right now that almost all these salvage regimens are quite similar. They have variable toxicity profiles, but if the treatment is given correctly and you look at the published literature, somewhere between 60% and 80% of the patients will likely be in remission after salvage chemotherapy. As defined as a negative PET, based upon standard criteria, those patients have a marked survival advantage, looking at published literature thus far.

As I’m maturing, I’ve been trying to treat patients with less aggressive salvage therapy to try to get them into remission. For example, in patients with early stage disease who relapse with non-bulky and non-widespread disease, I’d be more inclined to give an outpatient chemotherapy regimen. Patients with widespread, extranodal involvement, I’d be more inclined to give inpatient treatment off study. On clinical trials, that’s a different story, but we’ve published now, multiple times, that overwhelmingly a complete response (CR) prior to a stem cell transplant abrogates almost all the other prognostic factors.

DR. ANSELL: Right. Andy, if a patient had a response, but not a CR, or maybe only a modest improvement, would you say that’s a deal breaker for moving onto something like an autologous transplant?

DR. EVENS: I would say for the majority of patients, yes. There might be that patient who, depending on what they’ve received in the past—particularly if they have already received brentuximab vedotin—might be someone we still take to an autologous transplant.

There’s a significant minority you can still cure who are chemo-resistant, but I think I completely agree with Craig. In the era of novel therapeutics, that’s becoming less and less. As more options come on the table, I think if you really have somebody who’s chemotherapy resistant—that can be defined, I guess, as a positive PET, although I do think there are some gray zones in defining positive PET—I think it would be someone I would really look toward a novel therapeutic.

DR. ANSELL: Catherine, there have been some recent data about maintenance therapy after an autologous stem cell transplant. What’s your take on that?

DR. DIEFENBACH: I think the most recent data on maintenance therapy post autologous stem cell transplant comes from the AETHERA study,¹⁶ which Craig was the lead author on, and this investigated the question of whether using brentuximab vedotin as a consolidative therapy after transplant—as a maintenance therapy—improved PFS in this patient population.

The patients in this study who had relapsed disease were randomized between receiving brentuximab vedotin or being observed. Patients were treated for 16 cycles, which is approximately one year with this therapy, given every 3 weeks. Data from this study were in favor of brentuximab vedotin. The group that received brentuximab vedotin as opposed to being observed had a PFS of 42.9 months vs a PFS of approximately 24 months in the group that wasn’t treated with brentuximab vedotin.

This says a few interesting things. This demonstrates that most patients who are going into transplant are not doing so with optimal disease control. If all patients were going into transplant in a CR with only micrometastatic disease, there would not be such a stark difference between these arms. I think this study very nicely demonstrates that patients who benefit most strongly from the maintenance therapy are the patients who are considered to be the highest risk.

These are the patients with refractory disease who go into transplant with a high degree of tumor bulk, or patients who relapse within a short time—less than 12 months after their initial therapy—suggesting they didn’t really obtain optimal disease control with their therapy, or they had extranodal disease or disease outside of the lymph nodes affecting vital organs or bone marrow. These high-risk patients, based on these criteria, appear to be the ones who benefit the most from brentuximab maintenance. I think it gets a little tricky, however, because none of these patients receive brentuximab in their upfront therapy. So, going forward, it’s going to be an even harder question to ask—how are high-risk patients who receive brentuximab initially going to benefit from receiving a therapy that they relapsed from after receiving?

Getting brentuximab was not a free ride. There was a significantly higher amount of both sensory neuropathy, and about 20% of patients had motor neuropathy in the brentuximab group vs the non-brentuximab treated patients.

Finally, there was no difference yet—and this will still mature—in OS between the groups because the patients who didn’t get brentuximab were able to cross over and get it. This goes back to the old question with rituximab when rituximab maintenance was looked at. Is it better to receive brentuximab vedotin maintenance after transplant or is it better to receive it if you relapse after transplant? I think we won’t know the answer to that question for a few more years when we really see if the PFS translates into durable survival in the brentuximab treated group vs the non-brentuximab treated group. As Craig has alluded to with regard to the cost with respect to upfront therapy, I think this adds substantial costs subsequent to stem cell transplant. If we are going to use this therapy, I think we’ll have to be very clever in how we risk assess the patients who proceed to transplant, both prior to transplant and in terms of deciding whether they receive therapy.

There are actually efforts underway right now—internationally—to use better risk discrimination criteria for relapsed Hodgkin lymphoma to define a higher population of patients who are truly high risk, you might have the highest likelihood of benefiting from this sort of consolidative strategy.

DR. ANSELL: Craig, please comment. Catherine mentioned that the addition of brentuximab wasn’t without financial cost, and that there is also a toxicity cost. You led the study, what are your comments on the side effects of a year’s worth of brentuximab vedotin?

DR. MOSKOWITZ: I think, shockingly, the median number of doses that patients received on the study was 15, so almost a year or full course. In general, neuropathy is similar to every other single study that’s been looked at with single agent brentuximab. Peripheral neuropathy is real. For me, if a patient gets a dose reduction and the neuropathy does not improve, I would just stop the treatment. That’s how I practice.

I think the question Catherine raises is an extremely good one about patients who had a brentuximab vedotin pretransplant. Should they get brentuximab vedotin post-transplant? That’s something that’s clearly going to evolve, and the number of doses that a patient will receive post-transplant is going to evolve, but I think for the audience listening, this is here to stay for the next couple of years.

The FDA approved this August 17, so transplant physicians are going to initiate brentuximab vedotin therapy prior to the patient returning to their medical oncologist. It’s the medical oncologist who’s going to decide how many more cycles of brentuximab should be administered, because these folks would already have received three cycles by then.

Transplant physicians have to report 90-day efficacy data. In general, therefore, transplanters will see the patients up to around day 90. Brentuximab is administered between days 30 and 45 post-transplant, so by definition, the Hodgkin lymphoma patients who have met the criteria of the study are going to receive it. Medical oncologists need to decide what to do after that time point.

DR. DIEFENBACH: Craig, my question to you is given what the study showed—that the patients with the highest risk receive the most benefit—would you recommend giving this to everyone who undergoes a transplant, or really to the patients per the study who are considered to have at least one of these three risk factors?

DR. MOSKOWITZ: I only treat patients with maintenance who were potentially eligible for the AETHERA study. That means remission duration of less than one year, primary refractory disease, or extranodal involvement. If they did not meet those criteria, I do not recommend maintenance.

DR. ANSELL: Most of what we’ve discussed to far, with all of our therapeutic options, have been most likely to be utilized in younger patients—patients who can tolerate the intensive regimens, patients who can receive salvage therapy and can get a transplant. Elderly patients are a real challenge to treat. Andy, you’re an expert in this area—how do you manage a 70-year-old who presents with Hodgkin lymphoma? Are there some new options we should bear in mind as we think about these patients?

DR. EVENS: Yes, it’s definitely a challenging patient population. A recurring theme is there’s not a one-size-fits-all. Age 70 might fall right in the middle, but the definition of elderly, for better or for worse, has been greater than age 60 in most clinical studies and other analyses, but again, that 60-year-old vs the 85-year-old in a wheelchair will be approached differently.

Let’s say we take that sweet spot of someone in their early 70s who is still performing all their activities of daily living and most of their instrumental activities of daily living with a performance status of one—the quick answer off of a clinical study is I’d probably use AVD (AVBD without the bleomycin). We, and others, have reported the incidence of bleomycin lung toxicity and the number one risk factor is age. That’s part and parcel related to the renal clearance of bleomycin and knowing that that is a risk factor.

Are there other risk factors, such as preexisting lung disease, etc? Yes. We recently looked at what we called the contemporary era, meaning post 2000, when I was at Northwestern in Chicago—we collected close to 100 patients.¹⁷ It was more of a real-world population, it was whether or not you were on a clinical study, and a third of patients in that analysis had developed bleomycin lung toxicity. The mortality rate, if you developed bleomycin lung toxicity, was 30%.

If anyone’s ever had a patient die from that, they know it’s quite significant. We corroborated those data when we took a subset analyses out from E2406, the phase III randomized study of Stanford V vs ABVD. The rate of bleomycin lung was not quite as high. This again was a clinical study—probably a healthier population—but it was just under 30% with a mortality rate of just under 20%. To me it’s just too slippery of a slope. It’s hard, besides age, to predict who’s going to develop it. I think we’ve already mentioned some of the data. If we had to say which is the weakest link or the least potent of the ABVD, it would be the B.

That’s all for the clinical trial. Thankfully there are, now, clinical trials specifically carved out for this patient population of untreated older patients with Hodgkin lymphoma. We’re participating in a clinical trial with Paul Hamlin at Memorial Sloan Kettering and other sites where we’re utilizing a sequential approach integrating brentuximab vedotin. We rationalized that concurrent therapy would likely be too tough for these patients, so it’s designed in more of a window study where we start with two cycles of brentuximab vedotin given every 3 weeks, followed by chemotherapy, AVD, and then followed by consolidation therapy.

The study is not done yet. We have reported interim results at the recent Lugano meeting that was alluded to,¹⁸ and we showed yes, there’s still some toxicity, including to the brentuximab vedotin. But the disease related outcomes were phenomenal in the early report, upwards of 95%, which again is another theme in elderly Hodgkin that I didn’t talk about. One is the tolerability of therapy, and second is a strong sentiment—if not scientific hypothesis—that it’s a different disease biology, in other words, more aggressive. You see more mixalarity, Epstein Barr Virus related. Those are a couple of considerations. There are also studies out there that are looking—and especially the frail patients, maybe that 85 year old or so—what about single-agent novel therapeutics such as brentuximab vedotin or I’ve even heard through the grapevine now PD-1 inhibitors being tested as single agents in this patient population.

DR. ANSELL: Right, I think these are exciting times and there are data to be watched for in elderly patients. I want to talk about patients that have failed an autologous transplant. In the past, the typical next modality of therapy was an allogeneic (ALLO) transplant. Seeing as Craig is a guy that’s done a lot of transplants in the past—what do you see as the role of ALLO stem cell transplants? There are a lot of data now for new drugs in post-autologous failure patients, including brentuximab vedotin and PD-1 blockade. So, I guess the question is, has ALLO stem cell transplant for Hodgkin lymphoma gone away?

DR. MOSKOWITZ: Well, I see it as a slow, painful death to be perfectly honest.

DR. EVENS: No pun intended.

DR. MOSKOWITZ: No pun intended. We’ve been studying the checkpoint inhibitors as have you, Steve, for about 2 and a half years, and I will say that during this time, I have sent one patient to an ALLO stem cell transplant and that was a patient who really had a fairly poor response to nivolumab.

I find it very hard to pull the trigger, so to speak, to send a patient for an ALLO transplant now when the patients are receiving modern checkpoint inhibition and tolerating it so well with stable Hodgkin lymphoma that is not affecting their day-to-day life.

This, to me, is the most difficult question you’ve addressed so far on this teleconference. For someone who’s been doing this for a long time, I’m not sure at the present time who should get an ALLO transplant for Hodgkin lymphoma. I think it’s a difficult area. It’s unclear to me how to study it.

DR. ANSELL: Catherine, you’ve also done a lot of work with immune checkpoint inhibitors and combination studies. Give us your perspective on when to use brentuximab vedotin, when to use PD-1 inhibition, and when to use combinations.

DR. DIEFENBACH: I think most of these, Steve, are still research questions to a certain extent. Of these novel agents, the only one that is FDA approved for use in a relapse patient is brentuximab vedotin, which is approved for patients who have failed two or more chemotherapy regimens.

In practice, brentuximab is used much more commonly. If I have a patient who doesn’t have a huge amount of bulky relapse and is for some reason not a trial candidate I might well consider second line therapy with brentuximab as opposed to ifosfamide, carboplatin, and etoposide (ICE) chemotherapy. There are data both out of City of Hope and Sloan Kettering showing that the efficacy for brentuximab vedotin in second line is at least equivalent to the data we saw in later line with respect both to the CR rate and the overall response rate, if not better.^19,20

I think there’s an established role for brentuximab vedotin. There are other agents which are being used in the community that are not approved but are certainly looked at in combination or being used off-label, such as bendamustine, which also has published phase II data showing that it is also effective in relapsed Hodgkin lymphoma.²¹ I think really, with regard to second line, the goal is to get to a CR, and anything that can get you to a good CR to make autologous transplantation more effective is probably a good way to go. But I think the more interesting question is really how are we, in the future, going to design therapeutic strategies and therapeutic platforms that are really biologically based and relevant to Hodgkin lymphoma biology, rather than just taking something from column A and something from column B off the shelf?

I think the checkpoint inhibitors particularly speak to Hodgkin lymphoma biology, because what they’re doing—you have the PDL-1, which is expressed on the Hodgkin tumor cell (the HRS cell), and the PD-1 is actually on the T cells of the Hodgkin lymphoma microenvironment, and by blocking the ability of the T cells to interact with the Hodgkin lymphoma cells, you’re not actually directly killing anything.

What you’re doing is actually taking the activated T cells, which are switched off, and turning them back on the way you’d turn a light on and saying go do your job, go kill the HRS cells. We actually have a trial that’s open right now in which we’re combining brentuximab vedotin with a checkpoint inhibitor, ipilimumab, trying to do just that. We are trying to use the brentuximab to kill the HRS cells in bulk and release antigen and stimulate the T cells and we’re going to combine this with the PD-1 inhibitor nivolumab as well, and we’re planning to look at the triplet combination of dual checkpoint inhibition with ipilimumab and nivolumab with brentuximab and that study is open [Ipilimumab, Nivolumab, and Brentuximab Vedotin in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma; NCT01896999].

There are other studies ongoing, looking at brentuximab and nivolumab in combination as well. I think there’s a study planned, as Andy alluded to, in the elderly population as well as another study that is planned by pharmaceutical companies.

I think with regard to immune agents, we’ve only really scratched the surface, and everyone is very excited right now about these checkpoint inhibitors, but the immune microenvironment is composed of more than just some CD-4 cells that are sitting around in a switched off state. We have macrophages and dendritic cells and natural killer cells and I think there a lot of other exciting immunologic agents that are both being used right now in solid tumors and are being used pre-clinically that may have very exciting applicability for Hodgkin lymphoma.

Finally, there are the signaling agents—not to ignore them—like, the JAK/STAT inhibitors which is a pathway that’s highly upregulated in Hodgkin lymphoma cells and other agents, such as epigenetic agents, and I think going forward, the rational platforms are really going to combine these agents in intelligent ways and try to target the Hodgkin lymphoma in a way that can really obviate the need for ALLO transplant. I, as Craig, have the same issue with my patients who are on PD-1 inhibitor therapy. It’s very hard to see them doing so well and to really pull the trigger on referring them for an ALLO transplant.

DR. ANSELL: I’d like to summarize our roundtable discussion by saying These are exciting times. There are lots of changes in Hodgkin lymphoma that are developing as we watch, and the exciting thing is to see how we can optimize early stage therapy to minimize toxicity and maintain benefit., optimize advanced stage initial treatment to get the best results, again with the least toxicity, and then how to integrate these new agents with great promise into frontline therapies and salvage therapies so that, hopefully, down the line, we see more and more patients that are cured of their disease right away with initial treatment.

I want to thank Craig Moskowitz, Catherine Diefenbach, and Andy Evens for their participation.

References

1 Engert A, Plütschow A, Eich HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):640–652.

2 Eich HT, Diehl V, Görgen H, et al. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010;28(27):4199–4206.

3 Raemaekers JM, André MP, Federico M, et al. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014;32(12):1188–1194.

4 Barrington SF, O’Doherty MJ, Roberts TH, et al. PET-CT for staging and early response—results from the Response Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL) study. Hematol Oncol. 2013;31(Suppl. I):96–150. Abstract 18.

5 Behringer K, Goergen H, Hitz F, et al. for the German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse Tumortherapie. Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial. Lancet. 2015;385(9976):1418–1427.

6 Johnson PMW, et al. Response-adapted therapy based on interim FDG-PET scans in advanced Hodgkin lymphoma: 1st analysis of the safety of de-escalation & efficacy of escalation in the international RATHL study CRUK/07/033. Plenary Session: 13th International Conference on Malignant Lymphoma; June 17–20, 2015; Lugano, Switzerland.

7 Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med. 1998;339(21):1506–1514.

8 Diefenbach CS, Li H, Hong F, et al. Evaluation of the International Prognostic Score (IPS-7) and a Simpler Prognostic Score (IPS-3) for advanced Hodgkin lymphoma in the modern era. Br J Haematol. 2015. doi: 10.1111/bjh.13634. [Epub ahead of print]

9 Moccia AA, Donaldson J, Chhanabhai M, et al. International Prognostic Score in advanced-stage Hodgkin's lymphoma: altered utility in the modern era. J Clin Oncol. 2012;30(27):3383–3388.

10 Diehl V, Franklin J, Pfreundschuh M, et al. for the German Hodgkin's Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med. 2003;348(24):2386–2395.

11 Viviani S, Zinzani PL, Rambaldi A, et al for the Michelangelo Foundtaion; Gruppo Italiano di Terapie Innovative nei Linfomi; Intergruppo Italiano Linfomi. ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned. N Engl J Med. 2011;365(3):203–212.

12 Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 2012;30(18):2183–2189.

13 Younes A, Connors JM, Park SI, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol. 2013;14(13):1348–1356.

14 Gordon LI, Hong F, Fisher RI, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013;31(6):684–691.

15 Borchmann P, Eichenauer DA, Plütschow A, et al. Targeted BEACOPP variants in patients with newly diagnosed advanced stage classical Hodgkin lymphoma: interim results of a randomized phase II study. Blood. 2013;122(21)4344.

16 Moskowitz CH, Nadamanee A, Masszi T, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2015;385(9980):1853–1862.

17 Evens AM, Helenowski I, Ramsdale E, et al. A retrospective multicenter analysis of elderly Hodgkin lymphoma: outcomes and prognostic factors in the modern era. Blood. 2012;119(3):692–695. 

18 Evens AM, et al. Sequential brentuximab vedotin and AVD for older Hodgkin lymphoma patients: initial results from a phase 2 multicentre study. In:  Hematological Oncology – Special Issue: 13-ICML, 13th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano (Switzerland), 17–20 June, 2015. Abstract 89.

19 Chen RW, Palmer J, Siddiqi T, et al. Brentuximab vedotin as first line salvage therapy in relapsed/refractory HL. Poster presented at: 54th ASH Annual Meeting and Exposition; December 8–11, 2012; Atlanta, GA.

20 Moskowitz AJ, Schoder H, Yahalom J, et al. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncol. 2015;16(3):284–292.

21 Moskowitz AJ, Hamlin PA, Jr, Perales MA, et al. Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol. 2013;31(4):456–460.

Moderated by: Stephen Ansell, MD, PhD1

Discussants: Craig Moskowitz, MD2; Catherine Diefenbach, MD3; Andrew M. Evens, DO, MSc4

From Mayo Clinic, Rochester, MN¹; Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY²; NYU School of Medicine and NYU Perlmutter Cancer Center, New York, NY³; Tufts University School of Medicine and Tufts Medical Center, Boston, MA⁴

Address for correspondence: Stephen Ansell, MD, PhD, Mayo Clinic, 200 First Street SW #W10, Rochester, MN 55905

E-mail: [email protected]

Biographical sketch:

From Weill Medical College of Cornell University:

Dr. Moskowitz serves as principal investigator and co-investigator for a number of clinical trials aimed at improving the care of patients with lymphoma. His research has focused on improving the outcome of patients with poor-risk diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL). This effort has been conducted along two tracks. One effort is focused on improving therapy for patients with disease that has returned or is not responding to standard therapy (refractory disease), through the use of high-dose therapy and autologous stem cell transplantation as well as new agents that can be incorporated into such "salvage" therapy. The second is aimed at developing risk-adapted strategies to optimize the treatment of newly diagnosed DLBCL by using what we have learned in the relapsed and refractory setting. 

Dr. Moskowitz has been recognized for his research on a national level through multiple awards. He has lectured worldwide on lymphoma and stem cell transplantation. In addition, he is a member of the research council at MSKCC, and on the steering committees for the bi-annual international lymphoma conference in Lugano and international Hodgkin lymphoma conference in Cologne.

From NYU School of Medicine and NYU Perlmutter Cancer Center:

An alumna of the University of Pennsylvania School of Medicine, Dr. Diefenbach completed her internship and residency at the Johns Hopkins Hospital and her oncology fellowship at Memorial Sloan-Kettering Cancer Center, where she spent an additional year focusing on translational immunology.

Her scientific research focuses on the relationship between lymphoma and immunity; on developing novel and immune based treatment strategies for patients with relapsed lymphoma; and on biomarker discovery. She is currently leading a national clinical trial for relapsed Hodgkin lymphoma investigating the combination of the antibody drug conjugate brentuximab with the immune activating agents ipilimumab and nivolumab. 

Dr. Diefenbach directs the lymphoma clinical research within the Hematology/ Oncology Division at the Perlmutter Cancer Center. She is a member of the ECOG Lymphoma Committee, the NCI Lymphoma Steering Committee Clinical Trials Planning Meeting, and the Editorial Board of Clinical Cancer Research. Her research is supported by the Lymphoma Research Foundation, the American Cancer Society and the National Cancer Institute (NCI). 

From Tufts University School of Medicine and Tufts Medical Center:

DR. ANSELL: My name is Stephen Ansell, from Mayo Clinic, Rochester, Minnesota. I’m joined by Drs. Craig Moskowitz, Attending Physician at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Medical College of Cornell University, Catherine Diefenbach, Assistant Professor of Medicine at the NYU School of Medicine and the NYU Perlmutter Cancer Center, and Andy Evens, Professor of Medicine at Tufts University School of Medicine, and Faculty Member at Tufts Medical Center in Boston.

Welcome to all of you and thank you for participating in this medical roundtable discussion. The focus today is going to be on practical management of Hodgkin lymphoma. This is a very experienced group of roundtable participants whom I hope will give us valuable insights into some of the questions relating to managing Hodgkin lymphoma.

Let’s talk about patients with early stage Hodgkin lymphoma and discuss what we feel the standard management might be and how we would use positron emission tomographic (PET) scans to direct therapy. Craig, I’m going to ask you to start. Please discuss what your standard management of early stage Hodgkin lymphoma is and how you use PET scans to direct your treatment.

DR. MOSKOWITZ: I divide Hodgkin lymphoma, early stage, into three groups; favorable early stage, unfavorable early stage without tumor bulk, and stage two disease with tumor bulk. The standard management is well borne out these days from the German Hodgkin Lymphoma Study Group.^1,2 For early stage favorable Hodgkin lymphoma I treat men and women quite differently.

For men with stage IA or IIA, non-bulky disease, I tend to use standard treatment, which is short course combined modality therapy with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and involved-field radiation. I do not use PET imaging in that setting. For women, however, as you know, the median age is young in this patient population. I’ve adopted a RAPID approach for these folks. I give 3 months of chemotherapy and then repeat the PET scan and if the PET scan is negative I stop treatment. If the PET scan is positive, I treat the patient as per that study, which was one more cycle of chemotherapy and radiation. But unfavorable early-stage disease without tumor bulk, once again, the issue is, should patients get chemotherapy alone or should they get combined modality therapy?

If I’m giving combined modality therapy, I do not use PET imaging. If I’m using chemotherapy alone and if this is a patient eligible for a RAPID approach I treat as above. If the patient was not eligible for RAPID because they had stage IIB disease, I usually give full course chemotherapy and I do not use PET imaging.

For patients with bulky stage II disease, I treat based upon the randomized cooperative group study, which is four to six cycles of chemotherapy followed by radiation. I do not use PET imaging in that setting.

DR. ANSELL: Craig, thanks. Andy, do you actually escalate therapy at any time based on PET results, or deescalate therapy? We heard from Craig that he follows some of the RAPID guidelines. Give us your perspective.

DR. EVENS: I think they’re all good questions. In a way, it’s not one size fits all. I think it has to be a very individualized patient-by-patient treatment decision. In other words, I might approach a 19-year-old woman with a bulky mediastinal mass differently than a 45-year-old man with a right cervical lymph node. This is one important point to convey. In terms of PET-adapted, I think it is evolving. The question is, is there any actionable evidence to go on?

In terms of where there are more data, which is in early negativity in terms of PET-2 negativity, there have been a couple publications alluded to—RAPID and the European Organisation for Research and Treatment of Cancer (EORTC)³—and I’m not sure those data changed the opinion if we didn’t have an early negative PET scan. We know, without an early negative PET scan, that patients who do not receive consolidative radiation have a small improvement in progression-free survival (PFS) and no difference in overall survival (OS).

What both of those studies showed is that basically persists. That margin of difference might be a little less—instead of 6%–8% difference in PFS, it might now be 4%–6%, but both studies proved to be not noninferior, so I’m not quite sure that has changed how I treat someone. In other words, an early negative PET scan. For PET positivity, the data are really evolving. I think, before the Lugano meeting this past June I would have said no.

 I just saw a very recent second opinion on a younger patient in her mid-20s who had a bulky mediastinal mass, and then after two cycles was definitely better, but still PET positive, defined as it was a smidge greater than the liver, and the data that emanated from Lugano on early PET positive showed not only a PFS advantage, but a borderline OS, and that, of course, would be a game changer if PET-adapted therapy is pointing toward an OS advantage.

DR. ANSELL: Catherine, what’s your sense of the role of radiation therapy in early stage Hodgkin lymphoma?

DR. DIEFENBACH: As Andy said, the role of PET to stratify early stage patients is evolving. Another study that was reported in Lugano was the Response-adjusted Therapy for Hodgkin Lymphoma (RATHL) study⁴ where it appeared that for patients who had an early PET negative, the bleomycin could be omitted and the patients ended up with a PFS that was equivalent to patients who did not have bleomycin omitted. The decision of combined modality therapy vs standard therapy—I think Andy and Craig put it really well—will have to be individualized to the patient’s situation: specifically, to their age, sex, bulk of disease, and response after early disease assessment.

DR. MOSKOWITZ: That’s why it’s so hard to study this patient population. You have three folks on the phone and we’re all treating patients differently with an individualized approach. It’s almost impossible to come up with a clinical trial that everybody would be comfortable with in this patient population, which is why we have difficulty in writing one, which is disappointing.

DR. ANSELL: Craig, I wanted to circle back to you. The German Hodgkin Lymphoma Study Group has shown that if you omit bleomycin there is a slight decrease in outcome;⁵ however, the RATHL trial would suggest maybe not.⁶ Has that impacted your practice at all? Do you omit bleomycin in your regimens or do you use it standardly?

DR. MOSKOWITZ: Well, RATHL is for advanced stage disease and I’ve already stopped giving bleomycin to patients who are PET negative after 2 months of ABVD based on that approach; but I do not omit bleomycin for an early stage disease based upon the results from the German Hodgkin Lymphoma Study Group. We’re not giving full course chemotherapy in the early stage setting, so I’m willing to give the appropriate number of cycles, at least for now.

DR. ANSELL: Thanks for your perspectives. I think as it was pointed out, there’s a lot of individualization here and we still have an evolving role of PET scanning. Also, there are multiple new agents we’ll begin to talk about later in the program that may impact things further. So, I think this remains an area where it’s quite challenging to determine the optimal approach.

I want to turn our attention to talk about patients with advanced stage disease—predominantly stage III and IV disease. Catherine, how do you treat patients with advanced stage disease? What’s your approach, and as new agents are coming along, agents like brentuximab vedotin, where do you think they fit into your approach?

DR. DIEFENBACH: Just as Craig said, there isn’t really a one-size-fits-all approach to advanced-stage patients either. Just as early-stage patients are divided into at least three groups, we look at advanced-stage patients as a very heterogeneous population. One of the ways we stratify advanced-stage patients is based on what we call their risk score.

Traditionally, we’ve used the Hasenclever risk score—or the International Prognostic Score (IPS)⁷—which looks at seven clinical factors to get a sense of how these advanced-stage patients are going to do in terms of their PFS and OS.⁷ More recently, we have a manuscript where we’re looking in the modern era at using a streamlined score with only three of these factors instead of seven factors⁸ and the group from British Columbia has showed that, while this Hasenclever risk score is still relevant,⁹ it looks in the modern era with modern chemotherapy that it may be less helpful than it previously was, because the patients who did much worse are doing better, so the curves are narrowed.

Nonetheless, biologically and clinically, there’s a big difference between advanced-stage patients who have zero to two risk factors and advanced-stage patients who have five, six, or seven risk factors. The standard of care for treatment for advanced-stage patients both in the US and internationally has been either the chemotherapy regimen of ABVD or the chemotherapy regimen of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP).^10,11 There has been a controversy between those who prefer escalated BEACOPP and those who prefer ABVD. Escalated BEACOPP has a superior PFS to ABVD, which didn’t necessarily translate into an OS benefit, and patients who fail ABVD may be salvaged with stem cell transplant and second line chemotherapy and stem cell transplant.

Patients with escalated BEACOPP also have substantial therapy-related toxicity that patients with ABVD do not have, such as infertility and myelosuppression, higher rates of neutropenic fever, and higher rates of secondary leukemia, so there’s a cost associated with being treated with escalated BEACOPP that’s not associated with ABVD. With both regimens, the cure rate is approximately 75%–80%, so those who favor ABVD—I would consider myself one of them—would argue that you spare a certain number of patients who are salvaged with ABVD and who are cured unnecessary toxicity with the escalated BEACOPP. Those who are in favor of escalated BEACOPP for all patients would probably argue that an increased PFS should translate into an increased OS, and there have in fact been meta-analyses that show improved OS in some older trials with BEACOPP compared to ABVD, but this is a meta-analysis across many different trials.

More recently, brentuximab vedotin—an antibody drug conjugate, against CD30, which is expressed on the Hodgkin Reed-Sternberg (HRS) cell—combined with auristatin—a taxane-like cytotoxic chemotherapy—which acts like a Trojan horse, is delivered to the HRS cell, taken up by the HRS cell and then blows up the HRS cell while sparing, to a large extent, the microenvironment, has been incorporated into upfront therapy with ABVD.

Brentuximab was approved by the Food and Drug Administration (FDA) to treat relapsed Hodgkin lymphoma based on the pivotal study, which had an overall response rate of approximately 75% for relapsed patients.¹² Based on this it was incorporated into upfront therapy. There was a phase I study which I think, Steve, you actually led, which combined ABVD with brentuximab vedotin.¹³ This, however, resulted in excessive pulmonary toxicity secondary to bleomycin, so bleomycin was then omitted. The data were reported at the American Society of Hematology (ASH) meeting and showed a 3-year failure free survival of 96% and OS of 100%, which is extremely impressive in this population. The Phase 3 Frontline Therapy Trial in Patients With Advanced Classical Hodgkin Lymphoma (ECHELON) [NCT01712490] is currently underway and should complete accrual this year.

I think that these data will certainly help to answer the question of whether incorporating brentuximab into the upfront regimen of ABVD can improve both PFS and OS for these patients and perhaps put BEACOPP, finally, to rest.

DR. ANSELL: Andy, do you have a place in your practice where you think escalated BEACOPP has a role?

DR. EVENS: The quick answer is yes, but that sliver of practice is extremely small, and as time is going on, it’s getting smaller. I think in the pre-response adapted era—5 to 10 years ago when BEACOPP was first published—it did show an OS advantage, but many people would argue the comparator or COPP/ABVD arm isn’t equivalent, so to speak, to contemporary ABVD.

I was using it mainly in patients with high IPS—patients who had a five, six, or seven. That, frankly, is not a large percent of the patient population. Now, in the PET-adapted, we don’t quite have that actionable evidence, as much has accumulated quite yet, as early stage disease. Even in the patients now with high IPS, I have to admit, I’m really starting with ABVD in everyone and only considering escalating in patients who have a positive PET scan, which I guess in my practice is somewhat lower than the clinical trial data.

The clinical trial data in advanced-stage disease would say that’s 15%–20% of the patients.¹⁴ I tend to find it’s closer in the 5% range. I think part of that is viewing the PET-adapted part we keep talking about—it can’t be viewed in a vacuum, meaning you shouldn’t review a report. You should sit side-by-side with your radiologist and try to review that scan, and while doing that, have a clear meaning of what defines PET positive and PET negative, because almost every study we talked about has it slightly different. Where’s the cut point? Is it at the liver—meaning a Deauville score of four or five—or is it less in the liver, etc? So, I think those types of things are very important to understand and appreciate when treating the patients.

DR. DIEFENBACH: Andy, I completely agree with you and I also would have a role for BEACOPP in a patient who was not responding to ABVD with interim scans. I also, at that time, if the patient was by PET/computed tomography unequivocally refractory, I would consider clinical trial probably in the same vein as the escalated BEACOPP. So, I agree with Andy that I have a sliver of patients for whom I do consider escalated BEACOPP, but that is a very small sliver.

DR. ANSELL: Craig, what’s your comment about modifications that are happening, even to escalated BEACOPP? The BrECADD regimen is incorporating new agents like brentuximab vedotin.¹⁵ What’s your thinking about that regimen?

DR. MOSKOWITZ: I don’t treat patients off protocol with protocol based treatment, so my familiarity with it is low. Just to digress for one second, I think that I have definitely changed my practice and I would say that I used to give BEACOPP quite a bit for patients with four to seven risk factors, which is about 20% of the patient population. I think, based upon two fairly large studies that will have about 1700 patients on, the RATHL study and the intergroup study in the United States—it’s fairly clear—to me at least—that one can start with ABVD chemotherapy.

Since 80% of the patients have a negative interim PET scan, despite the number of pre-treatment risk factors they have, you’re really limiting the number of patients who get crossed over to a more complicated program, so I’ve been using that approach. I’m very comfortable with it.

The issue of giving brentuximab vedotin with AVD as part of primary therapy is, once again, investigational, and I have many concerns about the cost of that treatment program and it’s applicability worldwide even if the study is positive.

DR. ANSELL: I think that’s a good point. One of the things I find very interesting as we talk about the escalated BEACOPP vs. ABVD comparison is that as brentuximab vedotin has been mixed into those two regimens, it’s almost as if those two regimens are coming toward each other. ABVD is being somewhat escalated in intensity and escalated BEACOPP being modified down. I think at the end of the day, we’re going to come to a combined approach that suits people on both sides of the intensity debate. Cost, however, is going to be an issue to make this an internationally usable regimen, so I think that’s a real challenge.

I want to pick up, Craig, on the point you made about risks of relapse and so on. When and if patients relapse, what do you use in your practice as the optimal salvage regimen? Also, I know you’re a big advocate for your patients to attain a complete remission before going to transplant, would you like to explain why?

DR. MOSKOWITZ: Once again my opinion about this has evolved over the years, but I think that I’m fairly comfortable right now that almost all these salvage regimens are quite similar. They have variable toxicity profiles, but if the treatment is given correctly and you look at the published literature, somewhere between 60% and 80% of the patients will likely be in remission after salvage chemotherapy. As defined as a negative PET, based upon standard criteria, those patients have a marked survival advantage, looking at published literature thus far.

As I’m maturing, I’ve been trying to treat patients with less aggressive salvage therapy to try to get them into remission. For example, in patients with early stage disease who relapse with non-bulky and non-widespread disease, I’d be more inclined to give an outpatient chemotherapy regimen. Patients with widespread, extranodal involvement, I’d be more inclined to give inpatient treatment off study. On clinical trials, that’s a different story, but we’ve published now, multiple times, that overwhelmingly a complete response (CR) prior to a stem cell transplant abrogates almost all the other prognostic factors.

DR. ANSELL: Right. Andy, if a patient had a response, but not a CR, or maybe only a modest improvement, would you say that’s a deal breaker for moving onto something like an autologous transplant?

DR. EVENS: I would say for the majority of patients, yes. There might be that patient who, depending on what they’ve received in the past—particularly if they have already received brentuximab vedotin—might be someone we still take to an autologous transplant.

There’s a significant minority you can still cure who are chemo-resistant, but I think I completely agree with Craig. In the era of novel therapeutics, that’s becoming less and less. As more options come on the table, I think if you really have somebody who’s chemotherapy resistant—that can be defined, I guess, as a positive PET, although I do think there are some gray zones in defining positive PET—I think it would be someone I would really look toward a novel therapeutic.

DR. ANSELL: Catherine, there have been some recent data about maintenance therapy after an autologous stem cell transplant. What’s your take on that?

DR. DIEFENBACH: I think the most recent data on maintenance therapy post autologous stem cell transplant comes from the AETHERA study,¹⁶ which Craig was the lead author on, and this investigated the question of whether using brentuximab vedotin as a consolidative therapy after transplant—as a maintenance therapy—improved PFS in this patient population.

The patients in this study who had relapsed disease were randomized between receiving brentuximab vedotin or being observed. Patients were treated for 16 cycles, which is approximately one year with this therapy, given every 3 weeks. Data from this study were in favor of brentuximab vedotin. The group that received brentuximab vedotin as opposed to being observed had a PFS of 42.9 months vs a PFS of approximately 24 months in the group that wasn’t treated with brentuximab vedotin.

This says a few interesting things. This demonstrates that most patients who are going into transplant are not doing so with optimal disease control. If all patients were going into transplant in a CR with only micrometastatic disease, there would not be such a stark difference between these arms. I think this study very nicely demonstrates that patients who benefit most strongly from the maintenance therapy are the patients who are considered to be the highest risk.

These are the patients with refractory disease who go into transplant with a high degree of tumor bulk, or patients who relapse within a short time—less than 12 months after their initial therapy—suggesting they didn’t really obtain optimal disease control with their therapy, or they had extranodal disease or disease outside of the lymph nodes affecting vital organs or bone marrow. These high-risk patients, based on these criteria, appear to be the ones who benefit the most from brentuximab maintenance. I think it gets a little tricky, however, because none of these patients receive brentuximab in their upfront therapy. So, going forward, it’s going to be an even harder question to ask—how are high-risk patients who receive brentuximab initially going to benefit from receiving a therapy that they relapsed from after receiving?

Getting brentuximab was not a free ride. There was a significantly higher amount of both sensory neuropathy, and about 20% of patients had motor neuropathy in the brentuximab group vs the non-brentuximab treated patients.

Finally, there was no difference yet—and this will still mature—in OS between the groups because the patients who didn’t get brentuximab were able to cross over and get it. This goes back to the old question with rituximab when rituximab maintenance was looked at. Is it better to receive brentuximab vedotin maintenance after transplant or is it better to receive it if you relapse after transplant? I think we won’t know the answer to that question for a few more years when we really see if the PFS translates into durable survival in the brentuximab treated group vs the non-brentuximab treated group. As Craig has alluded to with regard to the cost with respect to upfront therapy, I think this adds substantial costs subsequent to stem cell transplant. If we are going to use this therapy, I think we’ll have to be very clever in how we risk assess the patients who proceed to transplant, both prior to transplant and in terms of deciding whether they receive therapy.

There are actually efforts underway right now—internationally—to use better risk discrimination criteria for relapsed Hodgkin lymphoma to define a higher population of patients who are truly high risk, you might have the highest likelihood of benefiting from this sort of consolidative strategy.

DR. ANSELL: Craig, please comment. Catherine mentioned that the addition of brentuximab wasn’t without financial cost, and that there is also a toxicity cost. You led the study, what are your comments on the side effects of a year’s worth of brentuximab vedotin?

DR. MOSKOWITZ: I think, shockingly, the median number of doses that patients received on the study was 15, so almost a year or full course. In general, neuropathy is similar to every other single study that’s been looked at with single agent brentuximab. Peripheral neuropathy is real. For me, if a patient gets a dose reduction and the neuropathy does not improve, I would just stop the treatment. That’s how I practice.

I think the question Catherine raises is an extremely good one about patients who had a brentuximab vedotin pretransplant. Should they get brentuximab vedotin post-transplant? That’s something that’s clearly going to evolve, and the number of doses that a patient will receive post-transplant is going to evolve, but I think for the audience listening, this is here to stay for the next couple of years.

The FDA approved this August 17, so transplant physicians are going to initiate brentuximab vedotin therapy prior to the patient returning to their medical oncologist. It’s the medical oncologist who’s going to decide how many more cycles of brentuximab should be administered, because these folks would already have received three cycles by then.

Transplant physicians have to report 90-day efficacy data. In general, therefore, transplanters will see the patients up to around day 90. Brentuximab is administered between days 30 and 45 post-transplant, so by definition, the Hodgkin lymphoma patients who have met the criteria of the study are going to receive it. Medical oncologists need to decide what to do after that time point.

DR. DIEFENBACH: Craig, my question to you is given what the study showed—that the patients with the highest risk receive the most benefit—would you recommend giving this to everyone who undergoes a transplant, or really to the patients per the study who are considered to have at least one of these three risk factors?

DR. MOSKOWITZ: I only treat patients with maintenance who were potentially eligible for the AETHERA study. That means remission duration of less than one year, primary refractory disease, or extranodal involvement. If they did not meet those criteria, I do not recommend maintenance.

DR. ANSELL: Most of what we’ve discussed to far, with all of our therapeutic options, have been most likely to be utilized in younger patients—patients who can tolerate the intensive regimens, patients who can receive salvage therapy and can get a transplant. Elderly patients are a real challenge to treat. Andy, you’re an expert in this area—how do you manage a 70-year-old who presents with Hodgkin lymphoma? Are there some new options we should bear in mind as we think about these patients?

DR. EVENS: Yes, it’s definitely a challenging patient population. A recurring theme is there’s not a one-size-fits-all. Age 70 might fall right in the middle, but the definition of elderly, for better or for worse, has been greater than age 60 in most clinical studies and other analyses, but again, that 60-year-old vs the 85-year-old in a wheelchair will be approached differently.

Let’s say we take that sweet spot of someone in their early 70s who is still performing all their activities of daily living and most of their instrumental activities of daily living with a performance status of one—the quick answer off of a clinical study is I’d probably use AVD (AVBD without the bleomycin). We, and others, have reported the incidence of bleomycin lung toxicity and the number one risk factor is age. That’s part and parcel related to the renal clearance of bleomycin and knowing that that is a risk factor.

Are there other risk factors, such as preexisting lung disease, etc? Yes. We recently looked at what we called the contemporary era, meaning post 2000, when I was at Northwestern in Chicago—we collected close to 100 patients.¹⁷ It was more of a real-world population, it was whether or not you were on a clinical study, and a third of patients in that analysis had developed bleomycin lung toxicity. The mortality rate, if you developed bleomycin lung toxicity, was 30%.

If anyone’s ever had a patient die from that, they know it’s quite significant. We corroborated those data when we took a subset analyses out from E2406, the phase III randomized study of Stanford V vs ABVD. The rate of bleomycin lung was not quite as high. This again was a clinical study—probably a healthier population—but it was just under 30% with a mortality rate of just under 20%. To me it’s just too slippery of a slope. It’s hard, besides age, to predict who’s going to develop it. I think we’ve already mentioned some of the data. If we had to say which is the weakest link or the least potent of the ABVD, it would be the B.

That’s all for the clinical trial. Thankfully there are, now, clinical trials specifically carved out for this patient population of untreated older patients with Hodgkin lymphoma. We’re participating in a clinical trial with Paul Hamlin at Memorial Sloan Kettering and other sites where we’re utilizing a sequential approach integrating brentuximab vedotin. We rationalized that concurrent therapy would likely be too tough for these patients, so it’s designed in more of a window study where we start with two cycles of brentuximab vedotin given every 3 weeks, followed by chemotherapy, AVD, and then followed by consolidation therapy.

The study is not done yet. We have reported interim results at the recent Lugano meeting that was alluded to,¹⁸ and we showed yes, there’s still some toxicity, including to the brentuximab vedotin. But the disease related outcomes were phenomenal in the early report, upwards of 95%, which again is another theme in elderly Hodgkin that I didn’t talk about. One is the tolerability of therapy, and second is a strong sentiment—if not scientific hypothesis—that it’s a different disease biology, in other words, more aggressive. You see more mixalarity, Epstein Barr Virus related. Those are a couple of considerations. There are also studies out there that are looking—and especially the frail patients, maybe that 85 year old or so—what about single-agent novel therapeutics such as brentuximab vedotin or I’ve even heard through the grapevine now PD-1 inhibitors being tested as single agents in this patient population.

DR. ANSELL: Right, I think these are exciting times and there are data to be watched for in elderly patients. I want to talk about patients that have failed an autologous transplant. In the past, the typical next modality of therapy was an allogeneic (ALLO) transplant. Seeing as Craig is a guy that’s done a lot of transplants in the past—what do you see as the role of ALLO stem cell transplants? There are a lot of data now for new drugs in post-autologous failure patients, including brentuximab vedotin and PD-1 blockade. So, I guess the question is, has ALLO stem cell transplant for Hodgkin lymphoma gone away?

DR. MOSKOWITZ: Well, I see it as a slow, painful death to be perfectly honest.

DR. EVENS: No pun intended.

DR. MOSKOWITZ: No pun intended. We’ve been studying the checkpoint inhibitors as have you, Steve, for about 2 and a half years, and I will say that during this time, I have sent one patient to an ALLO stem cell transplant and that was a patient who really had a fairly poor response to nivolumab.

I find it very hard to pull the trigger, so to speak, to send a patient for an ALLO transplant now when the patients are receiving modern checkpoint inhibition and tolerating it so well with stable Hodgkin lymphoma that is not affecting their day-to-day life.

This, to me, is the most difficult question you’ve addressed so far on this teleconference. For someone who’s been doing this for a long time, I’m not sure at the present time who should get an ALLO transplant for Hodgkin lymphoma. I think it’s a difficult area. It’s unclear to me how to study it.

DR. ANSELL: Catherine, you’ve also done a lot of work with immune checkpoint inhibitors and combination studies. Give us your perspective on when to use brentuximab vedotin, when to use PD-1 inhibition, and when to use combinations.

DR. DIEFENBACH: I think most of these, Steve, are still research questions to a certain extent. Of these novel agents, the only one that is FDA approved for use in a relapse patient is brentuximab vedotin, which is approved for patients who have failed two or more chemotherapy regimens.

In practice, brentuximab is used much more commonly. If I have a patient who doesn’t have a huge amount of bulky relapse and is for some reason not a trial candidate I might well consider second line therapy with brentuximab as opposed to ifosfamide, carboplatin, and etoposide (ICE) chemotherapy. There are data both out of City of Hope and Sloan Kettering showing that the efficacy for brentuximab vedotin in second line is at least equivalent to the data we saw in later line with respect both to the CR rate and the overall response rate, if not better.^19,20

I think there’s an established role for brentuximab vedotin. There are other agents which are being used in the community that are not approved but are certainly looked at in combination or being used off-label, such as bendamustine, which also has published phase II data showing that it is also effective in relapsed Hodgkin lymphoma.²¹ I think really, with regard to second line, the goal is to get to a CR, and anything that can get you to a good CR to make autologous transplantation more effective is probably a good way to go. But I think the more interesting question is really how are we, in the future, going to design therapeutic strategies and therapeutic platforms that are really biologically based and relevant to Hodgkin lymphoma biology, rather than just taking something from column A and something from column B off the shelf?

I think the checkpoint inhibitors particularly speak to Hodgkin lymphoma biology, because what they’re doing—you have the PDL-1, which is expressed on the Hodgkin tumor cell (the HRS cell), and the PD-1 is actually on the T cells of the Hodgkin lymphoma microenvironment, and by blocking the ability of the T cells to interact with the Hodgkin lymphoma cells, you’re not actually directly killing anything.

What you’re doing is actually taking the activated T cells, which are switched off, and turning them back on the way you’d turn a light on and saying go do your job, go kill the HRS cells. We actually have a trial that’s open right now in which we’re combining brentuximab vedotin with a checkpoint inhibitor, ipilimumab, trying to do just that. We are trying to use the brentuximab to kill the HRS cells in bulk and release antigen and stimulate the T cells and we’re going to combine this with the PD-1 inhibitor nivolumab as well, and we’re planning to look at the triplet combination of dual checkpoint inhibition with ipilimumab and nivolumab with brentuximab and that study is open [Ipilimumab, Nivolumab, and Brentuximab Vedotin in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma; NCT01896999].

There are other studies ongoing, looking at brentuximab and nivolumab in combination as well. I think there’s a study planned, as Andy alluded to, in the elderly population as well as another study that is planned by pharmaceutical companies.

I think with regard to immune agents, we’ve only really scratched the surface, and everyone is very excited right now about these checkpoint inhibitors, but the immune microenvironment is composed of more than just some CD-4 cells that are sitting around in a switched off state. We have macrophages and dendritic cells and natural killer cells and I think there a lot of other exciting immunologic agents that are both being used right now in solid tumors and are being used pre-clinically that may have very exciting applicability for Hodgkin lymphoma.

Finally, there are the signaling agents—not to ignore them—like, the JAK/STAT inhibitors which is a pathway that’s highly upregulated in Hodgkin lymphoma cells and other agents, such as epigenetic agents, and I think going forward, the rational platforms are really going to combine these agents in intelligent ways and try to target the Hodgkin lymphoma in a way that can really obviate the need for ALLO transplant. I, as Craig, have the same issue with my patients who are on PD-1 inhibitor therapy. It’s very hard to see them doing so well and to really pull the trigger on referring them for an ALLO transplant.

DR. ANSELL: I’d like to summarize our roundtable discussion by saying These are exciting times. There are lots of changes in Hodgkin lymphoma that are developing as we watch, and the exciting thing is to see how we can optimize early stage therapy to minimize toxicity and maintain benefit., optimize advanced stage initial treatment to get the best results, again with the least toxicity, and then how to integrate these new agents with great promise into frontline therapies and salvage therapies so that, hopefully, down the line, we see more and more patients that are cured of their disease right away with initial treatment.

I want to thank Craig Moskowitz, Catherine Diefenbach, and Andy Evens for their participation.

References

1 Engert A, Plütschow A, Eich HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):640–652.

2 Eich HT, Diehl V, Görgen H, et al. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010;28(27):4199–4206.

3 Raemaekers JM, André MP, Federico M, et al. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014;32(12):1188–1194.

4 Barrington SF, O’Doherty MJ, Roberts TH, et al. PET-CT for staging and early response—results from the Response Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL) study. Hematol Oncol. 2013;31(Suppl. I):96–150. Abstract 18.

5 Behringer K, Goergen H, Hitz F, et al. for the German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse Tumortherapie. Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial. Lancet. 2015;385(9976):1418–1427.

6 Johnson PMW, et al. Response-adapted therapy based on interim FDG-PET scans in advanced Hodgkin lymphoma: 1st analysis of the safety of de-escalation & efficacy of escalation in the international RATHL study CRUK/07/033. Plenary Session: 13th International Conference on Malignant Lymphoma; June 17–20, 2015; Lugano, Switzerland.

7 Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med. 1998;339(21):1506–1514.

8 Diefenbach CS, Li H, Hong F, et al. Evaluation of the International Prognostic Score (IPS-7) and a Simpler Prognostic Score (IPS-3) for advanced Hodgkin lymphoma in the modern era. Br J Haematol. 2015. doi: 10.1111/bjh.13634. [Epub ahead of print]

9 Moccia AA, Donaldson J, Chhanabhai M, et al. International Prognostic Score in advanced-stage Hodgkin's lymphoma: altered utility in the modern era. J Clin Oncol. 2012;30(27):3383–3388.

10 Diehl V, Franklin J, Pfreundschuh M, et al. for the German Hodgkin's Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med. 2003;348(24):2386–2395.

11 Viviani S, Zinzani PL, Rambaldi A, et al for the Michelangelo Foundtaion; Gruppo Italiano di Terapie Innovative nei Linfomi; Intergruppo Italiano Linfomi. ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned. N Engl J Med. 2011;365(3):203–212.

12 Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 2012;30(18):2183–2189.

13 Younes A, Connors JM, Park SI, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol. 2013;14(13):1348–1356.

14 Gordon LI, Hong F, Fisher RI, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013;31(6):684–691.

15 Borchmann P, Eichenauer DA, Plütschow A, et al. Targeted BEACOPP variants in patients with newly diagnosed advanced stage classical Hodgkin lymphoma: interim results of a randomized phase II study. Blood. 2013;122(21)4344.

16 Moskowitz CH, Nadamanee A, Masszi T, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2015;385(9980):1853–1862.

17 Evens AM, Helenowski I, Ramsdale E, et al. A retrospective multicenter analysis of elderly Hodgkin lymphoma: outcomes and prognostic factors in the modern era. Blood. 2012;119(3):692–695. 

18 Evens AM, et al. Sequential brentuximab vedotin and AVD for older Hodgkin lymphoma patients: initial results from a phase 2 multicentre study. In:  Hematological Oncology – Special Issue: 13-ICML, 13th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano (Switzerland), 17–20 June, 2015. Abstract 89.

19 Chen RW, Palmer J, Siddiqi T, et al. Brentuximab vedotin as first line salvage therapy in relapsed/refractory HL. Poster presented at: 54th ASH Annual Meeting and Exposition; December 8–11, 2012; Atlanta, GA.

20 Moskowitz AJ, Schoder H, Yahalom J, et al. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncol. 2015;16(3):284–292.

21 Moskowitz AJ, Hamlin PA, Jr, Perales MA, et al. Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol. 2013;31(4):456–460.

Moderated by: Stephen Ansell, MD, PhD1

Discussants: Craig Moskowitz, MD2; Catherine Diefenbach, MD3; Andrew M. Evens, DO, MSc4

From Mayo Clinic, Rochester, MN¹; Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY²; NYU School of Medicine and NYU Perlmutter Cancer Center, New York, NY³; Tufts University School of Medicine and Tufts Medical Center, Boston, MA⁴

Address for correspondence: Stephen Ansell, MD, PhD, Mayo Clinic, 200 First Street SW #W10, Rochester, MN 55905

E-mail: [email protected]

Biographical sketch:

From Weill Medical College of Cornell University:

Dr. Moskowitz serves as principal investigator and co-investigator for a number of clinical trials aimed at improving the care of patients with lymphoma. His research has focused on improving the outcome of patients with poor-risk diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL). This effort has been conducted along two tracks. One effort is focused on improving therapy for patients with disease that has returned or is not responding to standard therapy (refractory disease), through the use of high-dose therapy and autologous stem cell transplantation as well as new agents that can be incorporated into such "salvage" therapy. The second is aimed at developing risk-adapted strategies to optimize the treatment of newly diagnosed DLBCL by using what we have learned in the relapsed and refractory setting. 

Dr. Moskowitz has been recognized for his research on a national level through multiple awards. He has lectured worldwide on lymphoma and stem cell transplantation. In addition, he is a member of the research council at MSKCC, and on the steering committees for the bi-annual international lymphoma conference in Lugano and international Hodgkin lymphoma conference in Cologne.

From NYU School of Medicine and NYU Perlmutter Cancer Center:

An alumna of the University of Pennsylvania School of Medicine, Dr. Diefenbach completed her internship and residency at the Johns Hopkins Hospital and her oncology fellowship at Memorial Sloan-Kettering Cancer Center, where she spent an additional year focusing on translational immunology.

Her scientific research focuses on the relationship between lymphoma and immunity; on developing novel and immune based treatment strategies for patients with relapsed lymphoma; and on biomarker discovery. She is currently leading a national clinical trial for relapsed Hodgkin lymphoma investigating the combination of the antibody drug conjugate brentuximab with the immune activating agents ipilimumab and nivolumab. 

Dr. Diefenbach directs the lymphoma clinical research within the Hematology/ Oncology Division at the Perlmutter Cancer Center. She is a member of the ECOG Lymphoma Committee, the NCI Lymphoma Steering Committee Clinical Trials Planning Meeting, and the Editorial Board of Clinical Cancer Research. Her research is supported by the Lymphoma Research Foundation, the American Cancer Society and the National Cancer Institute (NCI). 

From Tufts University School of Medicine and Tufts Medical Center:

DR. ANSELL: My name is Stephen Ansell, from Mayo Clinic, Rochester, Minnesota. I’m joined by Drs. Craig Moskowitz, Attending Physician at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Medical College of Cornell University, Catherine Diefenbach, Assistant Professor of Medicine at the NYU School of Medicine and the NYU Perlmutter Cancer Center, and Andy Evens, Professor of Medicine at Tufts University School of Medicine, and Faculty Member at Tufts Medical Center in Boston.

Welcome to all of you and thank you for participating in this medical roundtable discussion. The focus today is going to be on practical management of Hodgkin lymphoma. This is a very experienced group of roundtable participants whom I hope will give us valuable insights into some of the questions relating to managing Hodgkin lymphoma.

Let’s talk about patients with early stage Hodgkin lymphoma and discuss what we feel the standard management might be and how we would use positron emission tomographic (PET) scans to direct therapy. Craig, I’m going to ask you to start. Please discuss what your standard management of early stage Hodgkin lymphoma is and how you use PET scans to direct your treatment.

DR. MOSKOWITZ: I divide Hodgkin lymphoma, early stage, into three groups; favorable early stage, unfavorable early stage without tumor bulk, and stage two disease with tumor bulk. The standard management is well borne out these days from the German Hodgkin Lymphoma Study Group.^1,2 For early stage favorable Hodgkin lymphoma I treat men and women quite differently.

For men with stage IA or IIA, non-bulky disease, I tend to use standard treatment, which is short course combined modality therapy with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and involved-field radiation. I do not use PET imaging in that setting. For women, however, as you know, the median age is young in this patient population. I’ve adopted a RAPID approach for these folks. I give 3 months of chemotherapy and then repeat the PET scan and if the PET scan is negative I stop treatment. If the PET scan is positive, I treat the patient as per that study, which was one more cycle of chemotherapy and radiation. But unfavorable early-stage disease without tumor bulk, once again, the issue is, should patients get chemotherapy alone or should they get combined modality therapy?

If I’m giving combined modality therapy, I do not use PET imaging. If I’m using chemotherapy alone and if this is a patient eligible for a RAPID approach I treat as above. If the patient was not eligible for RAPID because they had stage IIB disease, I usually give full course chemotherapy and I do not use PET imaging.

For patients with bulky stage II disease, I treat based upon the randomized cooperative group study, which is four to six cycles of chemotherapy followed by radiation. I do not use PET imaging in that setting.

DR. ANSELL: Craig, thanks. Andy, do you actually escalate therapy at any time based on PET results, or deescalate therapy? We heard from Craig that he follows some of the RAPID guidelines. Give us your perspective.

DR. EVENS: I think they’re all good questions. In a way, it’s not one size fits all. I think it has to be a very individualized patient-by-patient treatment decision. In other words, I might approach a 19-year-old woman with a bulky mediastinal mass differently than a 45-year-old man with a right cervical lymph node. This is one important point to convey. In terms of PET-adapted, I think it is evolving. The question is, is there any actionable evidence to go on?

In terms of where there are more data, which is in early negativity in terms of PET-2 negativity, there have been a couple publications alluded to—RAPID and the European Organisation for Research and Treatment of Cancer (EORTC)³—and I’m not sure those data changed the opinion if we didn’t have an early negative PET scan. We know, without an early negative PET scan, that patients who do not receive consolidative radiation have a small improvement in progression-free survival (PFS) and no difference in overall survival (OS).

What both of those studies showed is that basically persists. That margin of difference might be a little less—instead of 6%–8% difference in PFS, it might now be 4%–6%, but both studies proved to be not noninferior, so I’m not quite sure that has changed how I treat someone. In other words, an early negative PET scan. For PET positivity, the data are really evolving. I think, before the Lugano meeting this past June I would have said no.

 I just saw a very recent second opinion on a younger patient in her mid-20s who had a bulky mediastinal mass, and then after two cycles was definitely better, but still PET positive, defined as it was a smidge greater than the liver, and the data that emanated from Lugano on early PET positive showed not only a PFS advantage, but a borderline OS, and that, of course, would be a game changer if PET-adapted therapy is pointing toward an OS advantage.

DR. ANSELL: Catherine, what’s your sense of the role of radiation therapy in early stage Hodgkin lymphoma?

DR. DIEFENBACH: As Andy said, the role of PET to stratify early stage patients is evolving. Another study that was reported in Lugano was the Response-adjusted Therapy for Hodgkin Lymphoma (RATHL) study⁴ where it appeared that for patients who had an early PET negative, the bleomycin could be omitted and the patients ended up with a PFS that was equivalent to patients who did not have bleomycin omitted. The decision of combined modality therapy vs standard therapy—I think Andy and Craig put it really well—will have to be individualized to the patient’s situation: specifically, to their age, sex, bulk of disease, and response after early disease assessment.

DR. MOSKOWITZ: That’s why it’s so hard to study this patient population. You have three folks on the phone and we’re all treating patients differently with an individualized approach. It’s almost impossible to come up with a clinical trial that everybody would be comfortable with in this patient population, which is why we have difficulty in writing one, which is disappointing.

DR. ANSELL: Craig, I wanted to circle back to you. The German Hodgkin Lymphoma Study Group has shown that if you omit bleomycin there is a slight decrease in outcome;⁵ however, the RATHL trial would suggest maybe not.⁶ Has that impacted your practice at all? Do you omit bleomycin in your regimens or do you use it standardly?

DR. MOSKOWITZ: Well, RATHL is for advanced stage disease and I’ve already stopped giving bleomycin to patients who are PET negative after 2 months of ABVD based on that approach; but I do not omit bleomycin for an early stage disease based upon the results from the German Hodgkin Lymphoma Study Group. We’re not giving full course chemotherapy in the early stage setting, so I’m willing to give the appropriate number of cycles, at least for now.

DR. ANSELL: Thanks for your perspectives. I think as it was pointed out, there’s a lot of individualization here and we still have an evolving role of PET scanning. Also, there are multiple new agents we’ll begin to talk about later in the program that may impact things further. So, I think this remains an area where it’s quite challenging to determine the optimal approach.

I want to turn our attention to talk about patients with advanced stage disease—predominantly stage III and IV disease. Catherine, how do you treat patients with advanced stage disease? What’s your approach, and as new agents are coming along, agents like brentuximab vedotin, where do you think they fit into your approach?

DR. DIEFENBACH: Just as Craig said, there isn’t really a one-size-fits-all approach to advanced-stage patients either. Just as early-stage patients are divided into at least three groups, we look at advanced-stage patients as a very heterogeneous population. One of the ways we stratify advanced-stage patients is based on what we call their risk score.

Traditionally, we’ve used the Hasenclever risk score—or the International Prognostic Score (IPS)⁷—which looks at seven clinical factors to get a sense of how these advanced-stage patients are going to do in terms of their PFS and OS.⁷ More recently, we have a manuscript where we’re looking in the modern era at using a streamlined score with only three of these factors instead of seven factors⁸ and the group from British Columbia has showed that, while this Hasenclever risk score is still relevant,⁹ it looks in the modern era with modern chemotherapy that it may be less helpful than it previously was, because the patients who did much worse are doing better, so the curves are narrowed.

Nonetheless, biologically and clinically, there’s a big difference between advanced-stage patients who have zero to two risk factors and advanced-stage patients who have five, six, or seven risk factors. The standard of care for treatment for advanced-stage patients both in the US and internationally has been either the chemotherapy regimen of ABVD or the chemotherapy regimen of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP).^10,11 There has been a controversy between those who prefer escalated BEACOPP and those who prefer ABVD. Escalated BEACOPP has a superior PFS to ABVD, which didn’t necessarily translate into an OS benefit, and patients who fail ABVD may be salvaged with stem cell transplant and second line chemotherapy and stem cell transplant.

Patients with escalated BEACOPP also have substantial therapy-related toxicity that patients with ABVD do not have, such as infertility and myelosuppression, higher rates of neutropenic fever, and higher rates of secondary leukemia, so there’s a cost associated with being treated with escalated BEACOPP that’s not associated with ABVD. With both regimens, the cure rate is approximately 75%–80%, so those who favor ABVD—I would consider myself one of them—would argue that you spare a certain number of patients who are salvaged with ABVD and who are cured unnecessary toxicity with the escalated BEACOPP. Those who are in favor of escalated BEACOPP for all patients would probably argue that an increased PFS should translate into an increased OS, and there have in fact been meta-analyses that show improved OS in some older trials with BEACOPP compared to ABVD, but this is a meta-analysis across many different trials.

More recently, brentuximab vedotin—an antibody drug conjugate, against CD30, which is expressed on the Hodgkin Reed-Sternberg (HRS) cell—combined with auristatin—a taxane-like cytotoxic chemotherapy—which acts like a Trojan horse, is delivered to the HRS cell, taken up by the HRS cell and then blows up the HRS cell while sparing, to a large extent, the microenvironment, has been incorporated into upfront therapy with ABVD.

Brentuximab was approved by the Food and Drug Administration (FDA) to treat relapsed Hodgkin lymphoma based on the pivotal study, which had an overall response rate of approximately 75% for relapsed patients.¹² Based on this it was incorporated into upfront therapy. There was a phase I study which I think, Steve, you actually led, which combined ABVD with brentuximab vedotin.¹³ This, however, resulted in excessive pulmonary toxicity secondary to bleomycin, so bleomycin was then omitted. The data were reported at the American Society of Hematology (ASH) meeting and showed a 3-year failure free survival of 96% and OS of 100%, which is extremely impressive in this population. The Phase 3 Frontline Therapy Trial in Patients With Advanced Classical Hodgkin Lymphoma (ECHELON) [NCT01712490] is currently underway and should complete accrual this year.

I think that these data will certainly help to answer the question of whether incorporating brentuximab into the upfront regimen of ABVD can improve both PFS and OS for these patients and perhaps put BEACOPP, finally, to rest.

DR. ANSELL: Andy, do you have a place in your practice where you think escalated BEACOPP has a role?

DR. EVENS: The quick answer is yes, but that sliver of practice is extremely small, and as time is going on, it’s getting smaller. I think in the pre-response adapted era—5 to 10 years ago when BEACOPP was first published—it did show an OS advantage, but many people would argue the comparator or COPP/ABVD arm isn’t equivalent, so to speak, to contemporary ABVD.

I was using it mainly in patients with high IPS—patients who had a five, six, or seven. That, frankly, is not a large percent of the patient population. Now, in the PET-adapted, we don’t quite have that actionable evidence, as much has accumulated quite yet, as early stage disease. Even in the patients now with high IPS, I have to admit, I’m really starting with ABVD in everyone and only considering escalating in patients who have a positive PET scan, which I guess in my practice is somewhat lower than the clinical trial data.

The clinical trial data in advanced-stage disease would say that’s 15%–20% of the patients.¹⁴ I tend to find it’s closer in the 5% range. I think part of that is viewing the PET-adapted part we keep talking about—it can’t be viewed in a vacuum, meaning you shouldn’t review a report. You should sit side-by-side with your radiologist and try to review that scan, and while doing that, have a clear meaning of what defines PET positive and PET negative, because almost every study we talked about has it slightly different. Where’s the cut point? Is it at the liver—meaning a Deauville score of four or five—or is it less in the liver, etc? So, I think those types of things are very important to understand and appreciate when treating the patients.

DR. DIEFENBACH: Andy, I completely agree with you and I also would have a role for BEACOPP in a patient who was not responding to ABVD with interim scans. I also, at that time, if the patient was by PET/computed tomography unequivocally refractory, I would consider clinical trial probably in the same vein as the escalated BEACOPP. So, I agree with Andy that I have a sliver of patients for whom I do consider escalated BEACOPP, but that is a very small sliver.

DR. ANSELL: Craig, what’s your comment about modifications that are happening, even to escalated BEACOPP? The BrECADD regimen is incorporating new agents like brentuximab vedotin.¹⁵ What’s your thinking about that regimen?

DR. MOSKOWITZ: I don’t treat patients off protocol with protocol based treatment, so my familiarity with it is low. Just to digress for one second, I think that I have definitely changed my practice and I would say that I used to give BEACOPP quite a bit for patients with four to seven risk factors, which is about 20% of the patient population. I think, based upon two fairly large studies that will have about 1700 patients on, the RATHL study and the intergroup study in the United States—it’s fairly clear—to me at least—that one can start with ABVD chemotherapy.

Since 80% of the patients have a negative interim PET scan, despite the number of pre-treatment risk factors they have, you’re really limiting the number of patients who get crossed over to a more complicated program, so I’ve been using that approach. I’m very comfortable with it.

The issue of giving brentuximab vedotin with AVD as part of primary therapy is, once again, investigational, and I have many concerns about the cost of that treatment program and it’s applicability worldwide even if the study is positive.

DR. ANSELL: I think that’s a good point. One of the things I find very interesting as we talk about the escalated BEACOPP vs. ABVD comparison is that as brentuximab vedotin has been mixed into those two regimens, it’s almost as if those two regimens are coming toward each other. ABVD is being somewhat escalated in intensity and escalated BEACOPP being modified down. I think at the end of the day, we’re going to come to a combined approach that suits people on both sides of the intensity debate. Cost, however, is going to be an issue to make this an internationally usable regimen, so I think that’s a real challenge.

I want to pick up, Craig, on the point you made about risks of relapse and so on. When and if patients relapse, what do you use in your practice as the optimal salvage regimen? Also, I know you’re a big advocate for your patients to attain a complete remission before going to transplant, would you like to explain why?

DR. MOSKOWITZ: Once again my opinion about this has evolved over the years, but I think that I’m fairly comfortable right now that almost all these salvage regimens are quite similar. They have variable toxicity profiles, but if the treatment is given correctly and you look at the published literature, somewhere between 60% and 80% of the patients will likely be in remission after salvage chemotherapy. As defined as a negative PET, based upon standard criteria, those patients have a marked survival advantage, looking at published literature thus far.

As I’m maturing, I’ve been trying to treat patients with less aggressive salvage therapy to try to get them into remission. For example, in patients with early stage disease who relapse with non-bulky and non-widespread disease, I’d be more inclined to give an outpatient chemotherapy regimen. Patients with widespread, extranodal involvement, I’d be more inclined to give inpatient treatment off study. On clinical trials, that’s a different story, but we’ve published now, multiple times, that overwhelmingly a complete response (CR) prior to a stem cell transplant abrogates almost all the other prognostic factors.

DR. ANSELL: Right. Andy, if a patient had a response, but not a CR, or maybe only a modest improvement, would you say that’s a deal breaker for moving onto something like an autologous transplant?

DR. EVENS: I would say for the majority of patients, yes. There might be that patient who, depending on what they’ve received in the past—particularly if they have already received brentuximab vedotin—might be someone we still take to an autologous transplant.

There’s a significant minority you can still cure who are chemo-resistant, but I think I completely agree with Craig. In the era of novel therapeutics, that’s becoming less and less. As more options come on the table, I think if you really have somebody who’s chemotherapy resistant—that can be defined, I guess, as a positive PET, although I do think there are some gray zones in defining positive PET—I think it would be someone I would really look toward a novel therapeutic.

DR. ANSELL: Catherine, there have been some recent data about maintenance therapy after an autologous stem cell transplant. What’s your take on that?

DR. DIEFENBACH: I think the most recent data on maintenance therapy post autologous stem cell transplant comes from the AETHERA study,¹⁶ which Craig was the lead author on, and this investigated the question of whether using brentuximab vedotin as a consolidative therapy after transplant—as a maintenance therapy—improved PFS in this patient population.

The patients in this study who had relapsed disease were randomized between receiving brentuximab vedotin or being observed. Patients were treated for 16 cycles, which is approximately one year with this therapy, given every 3 weeks. Data from this study were in favor of brentuximab vedotin. The group that received brentuximab vedotin as opposed to being observed had a PFS of 42.9 months vs a PFS of approximately 24 months in the group that wasn’t treated with brentuximab vedotin.

This says a few interesting things. This demonstrates that most patients who are going into transplant are not doing so with optimal disease control. If all patients were going into transplant in a CR with only micrometastatic disease, there would not be such a stark difference between these arms. I think this study very nicely demonstrates that patients who benefit most strongly from the maintenance therapy are the patients who are considered to be the highest risk.

These are the patients with refractory disease who go into transplant with a high degree of tumor bulk, or patients who relapse within a short time—less than 12 months after their initial therapy—suggesting they didn’t really obtain optimal disease control with their therapy, or they had extranodal disease or disease outside of the lymph nodes affecting vital organs or bone marrow. These high-risk patients, based on these criteria, appear to be the ones who benefit the most from brentuximab maintenance. I think it gets a little tricky, however, because none of these patients receive brentuximab in their upfront therapy. So, going forward, it’s going to be an even harder question to ask—how are high-risk patients who receive brentuximab initially going to benefit from receiving a therapy that they relapsed from after receiving?

Getting brentuximab was not a free ride. There was a significantly higher amount of both sensory neuropathy, and about 20% of patients had motor neuropathy in the brentuximab group vs the non-brentuximab treated patients.

Finally, there was no difference yet—and this will still mature—in OS between the groups because the patients who didn’t get brentuximab were able to cross over and get it. This goes back to the old question with rituximab when rituximab maintenance was looked at. Is it better to receive brentuximab vedotin maintenance after transplant or is it better to receive it if you relapse after transplant? I think we won’t know the answer to that question for a few more years when we really see if the PFS translates into durable survival in the brentuximab treated group vs the non-brentuximab treated group. As Craig has alluded to with regard to the cost with respect to upfront therapy, I think this adds substantial costs subsequent to stem cell transplant. If we are going to use this therapy, I think we’ll have to be very clever in how we risk assess the patients who proceed to transplant, both prior to transplant and in terms of deciding whether they receive therapy.

There are actually efforts underway right now—internationally—to use better risk discrimination criteria for relapsed Hodgkin lymphoma to define a higher population of patients who are truly high risk, you might have the highest likelihood of benefiting from this sort of consolidative strategy.

DR. ANSELL: Craig, please comment. Catherine mentioned that the addition of brentuximab wasn’t without financial cost, and that there is also a toxicity cost. You led the study, what are your comments on the side effects of a year’s worth of brentuximab vedotin?

DR. MOSKOWITZ: I think, shockingly, the median number of doses that patients received on the study was 15, so almost a year or full course. In general, neuropathy is similar to every other single study that’s been looked at with single agent brentuximab. Peripheral neuropathy is real. For me, if a patient gets a dose reduction and the neuropathy does not improve, I would just stop the treatment. That’s how I practice.

I think the question Catherine raises is an extremely good one about patients who had a brentuximab vedotin pretransplant. Should they get brentuximab vedotin post-transplant? That’s something that’s clearly going to evolve, and the number of doses that a patient will receive post-transplant is going to evolve, but I think for the audience listening, this is here to stay for the next couple of years.

The FDA approved this August 17, so transplant physicians are going to initiate brentuximab vedotin therapy prior to the patient returning to their medical oncologist. It’s the medical oncologist who’s going to decide how many more cycles of brentuximab should be administered, because these folks would already have received three cycles by then.

Transplant physicians have to report 90-day efficacy data. In general, therefore, transplanters will see the patients up to around day 90. Brentuximab is administered between days 30 and 45 post-transplant, so by definition, the Hodgkin lymphoma patients who have met the criteria of the study are going to receive it. Medical oncologists need to decide what to do after that time point.

DR. DIEFENBACH: Craig, my question to you is given what the study showed—that the patients with the highest risk receive the most benefit—would you recommend giving this to everyone who undergoes a transplant, or really to the patients per the study who are considered to have at least one of these three risk factors?

DR. MOSKOWITZ: I only treat patients with maintenance who were potentially eligible for the AETHERA study. That means remission duration of less than one year, primary refractory disease, or extranodal involvement. If they did not meet those criteria, I do not recommend maintenance.

DR. ANSELL: Most of what we’ve discussed to far, with all of our therapeutic options, have been most likely to be utilized in younger patients—patients who can tolerate the intensive regimens, patients who can receive salvage therapy and can get a transplant. Elderly patients are a real challenge to treat. Andy, you’re an expert in this area—how do you manage a 70-year-old who presents with Hodgkin lymphoma? Are there some new options we should bear in mind as we think about these patients?

DR. EVENS: Yes, it’s definitely a challenging patient population. A recurring theme is there’s not a one-size-fits-all. Age 70 might fall right in the middle, but the definition of elderly, for better or for worse, has been greater than age 60 in most clinical studies and other analyses, but again, that 60-year-old vs the 85-year-old in a wheelchair will be approached differently.

Let’s say we take that sweet spot of someone in their early 70s who is still performing all their activities of daily living and most of their instrumental activities of daily living with a performance status of one—the quick answer off of a clinical study is I’d probably use AVD (AVBD without the bleomycin). We, and others, have reported the incidence of bleomycin lung toxicity and the number one risk factor is age. That’s part and parcel related to the renal clearance of bleomycin and knowing that that is a risk factor.

Are there other risk factors, such as preexisting lung disease, etc? Yes. We recently looked at what we called the contemporary era, meaning post 2000, when I was at Northwestern in Chicago—we collected close to 100 patients.¹⁷ It was more of a real-world population, it was whether or not you were on a clinical study, and a third of patients in that analysis had developed bleomycin lung toxicity. The mortality rate, if you developed bleomycin lung toxicity, was 30%.

If anyone’s ever had a patient die from that, they know it’s quite significant. We corroborated those data when we took a subset analyses out from E2406, the phase III randomized study of Stanford V vs ABVD. The rate of bleomycin lung was not quite as high. This again was a clinical study—probably a healthier population—but it was just under 30% with a mortality rate of just under 20%. To me it’s just too slippery of a slope. It’s hard, besides age, to predict who’s going to develop it. I think we’ve already mentioned some of the data. If we had to say which is the weakest link or the least potent of the ABVD, it would be the B.

That’s all for the clinical trial. Thankfully there are, now, clinical trials specifically carved out for this patient population of untreated older patients with Hodgkin lymphoma. We’re participating in a clinical trial with Paul Hamlin at Memorial Sloan Kettering and other sites where we’re utilizing a sequential approach integrating brentuximab vedotin. We rationalized that concurrent therapy would likely be too tough for these patients, so it’s designed in more of a window study where we start with two cycles of brentuximab vedotin given every 3 weeks, followed by chemotherapy, AVD, and then followed by consolidation therapy.

The study is not done yet. We have reported interim results at the recent Lugano meeting that was alluded to,¹⁸ and we showed yes, there’s still some toxicity, including to the brentuximab vedotin. But the disease related outcomes were phenomenal in the early report, upwards of 95%, which again is another theme in elderly Hodgkin that I didn’t talk about. One is the tolerability of therapy, and second is a strong sentiment—if not scientific hypothesis—that it’s a different disease biology, in other words, more aggressive. You see more mixalarity, Epstein Barr Virus related. Those are a couple of considerations. There are also studies out there that are looking—and especially the frail patients, maybe that 85 year old or so—what about single-agent novel therapeutics such as brentuximab vedotin or I’ve even heard through the grapevine now PD-1 inhibitors being tested as single agents in this patient population.

DR. ANSELL: Right, I think these are exciting times and there are data to be watched for in elderly patients. I want to talk about patients that have failed an autologous transplant. In the past, the typical next modality of therapy was an allogeneic (ALLO) transplant. Seeing as Craig is a guy that’s done a lot of transplants in the past—what do you see as the role of ALLO stem cell transplants? There are a lot of data now for new drugs in post-autologous failure patients, including brentuximab vedotin and PD-1 blockade. So, I guess the question is, has ALLO stem cell transplant for Hodgkin lymphoma gone away?

DR. MOSKOWITZ: Well, I see it as a slow, painful death to be perfectly honest.

DR. EVENS: No pun intended.

DR. MOSKOWITZ: No pun intended. We’ve been studying the checkpoint inhibitors as have you, Steve, for about 2 and a half years, and I will say that during this time, I have sent one patient to an ALLO stem cell transplant and that was a patient who really had a fairly poor response to nivolumab.

I find it very hard to pull the trigger, so to speak, to send a patient for an ALLO transplant now when the patients are receiving modern checkpoint inhibition and tolerating it so well with stable Hodgkin lymphoma that is not affecting their day-to-day life.

This, to me, is the most difficult question you’ve addressed so far on this teleconference. For someone who’s been doing this for a long time, I’m not sure at the present time who should get an ALLO transplant for Hodgkin lymphoma. I think it’s a difficult area. It’s unclear to me how to study it.

DR. ANSELL: Catherine, you’ve also done a lot of work with immune checkpoint inhibitors and combination studies. Give us your perspective on when to use brentuximab vedotin, when to use PD-1 inhibition, and when to use combinations.

DR. DIEFENBACH: I think most of these, Steve, are still research questions to a certain extent. Of these novel agents, the only one that is FDA approved for use in a relapse patient is brentuximab vedotin, which is approved for patients who have failed two or more chemotherapy regimens.

In practice, brentuximab is used much more commonly. If I have a patient who doesn’t have a huge amount of bulky relapse and is for some reason not a trial candidate I might well consider second line therapy with brentuximab as opposed to ifosfamide, carboplatin, and etoposide (ICE) chemotherapy. There are data both out of City of Hope and Sloan Kettering showing that the efficacy for brentuximab vedotin in second line is at least equivalent to the data we saw in later line with respect both to the CR rate and the overall response rate, if not better.^19,20

I think there’s an established role for brentuximab vedotin. There are other agents which are being used in the community that are not approved but are certainly looked at in combination or being used off-label, such as bendamustine, which also has published phase II data showing that it is also effective in relapsed Hodgkin lymphoma.²¹ I think really, with regard to second line, the goal is to get to a CR, and anything that can get you to a good CR to make autologous transplantation more effective is probably a good way to go. But I think the more interesting question is really how are we, in the future, going to design therapeutic strategies and therapeutic platforms that are really biologically based and relevant to Hodgkin lymphoma biology, rather than just taking something from column A and something from column B off the shelf?

I think the checkpoint inhibitors particularly speak to Hodgkin lymphoma biology, because what they’re doing—you have the PDL-1, which is expressed on the Hodgkin tumor cell (the HRS cell), and the PD-1 is actually on the T cells of the Hodgkin lymphoma microenvironment, and by blocking the ability of the T cells to interact with the Hodgkin lymphoma cells, you’re not actually directly killing anything.

What you’re doing is actually taking the activated T cells, which are switched off, and turning them back on the way you’d turn a light on and saying go do your job, go kill the HRS cells. We actually have a trial that’s open right now in which we’re combining brentuximab vedotin with a checkpoint inhibitor, ipilimumab, trying to do just that. We are trying to use the brentuximab to kill the HRS cells in bulk and release antigen and stimulate the T cells and we’re going to combine this with the PD-1 inhibitor nivolumab as well, and we’re planning to look at the triplet combination of dual checkpoint inhibition with ipilimumab and nivolumab with brentuximab and that study is open [Ipilimumab, Nivolumab, and Brentuximab Vedotin in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma; NCT01896999].

There are other studies ongoing, looking at brentuximab and nivolumab in combination as well. I think there’s a study planned, as Andy alluded to, in the elderly population as well as another study that is planned by pharmaceutical companies.

I think with regard to immune agents, we’ve only really scratched the surface, and everyone is very excited right now about these checkpoint inhibitors, but the immune microenvironment is composed of more than just some CD-4 cells that are sitting around in a switched off state. We have macrophages and dendritic cells and natural killer cells and I think there a lot of other exciting immunologic agents that are both being used right now in solid tumors and are being used pre-clinically that may have very exciting applicability for Hodgkin lymphoma.

Finally, there are the signaling agents—not to ignore them—like, the JAK/STAT inhibitors which is a pathway that’s highly upregulated in Hodgkin lymphoma cells and other agents, such as epigenetic agents, and I think going forward, the rational platforms are really going to combine these agents in intelligent ways and try to target the Hodgkin lymphoma in a way that can really obviate the need for ALLO transplant. I, as Craig, have the same issue with my patients who are on PD-1 inhibitor therapy. It’s very hard to see them doing so well and to really pull the trigger on referring them for an ALLO transplant.

DR. ANSELL: I’d like to summarize our roundtable discussion by saying These are exciting times. There are lots of changes in Hodgkin lymphoma that are developing as we watch, and the exciting thing is to see how we can optimize early stage therapy to minimize toxicity and maintain benefit., optimize advanced stage initial treatment to get the best results, again with the least toxicity, and then how to integrate these new agents with great promise into frontline therapies and salvage therapies so that, hopefully, down the line, we see more and more patients that are cured of their disease right away with initial treatment.

I want to thank Craig Moskowitz, Catherine Diefenbach, and Andy Evens for their participation.

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9 Moccia AA, Donaldson J, Chhanabhai M, et al. International Prognostic Score in advanced-stage Hodgkin's lymphoma: altered utility in the modern era. J Clin Oncol. 2012;30(27):3383–3388.

10 Diehl V, Franklin J, Pfreundschuh M, et al. for the German Hodgkin's Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med. 2003;348(24):2386–2395.

11 Viviani S, Zinzani PL, Rambaldi A, et al for the Michelangelo Foundtaion; Gruppo Italiano di Terapie Innovative nei Linfomi; Intergruppo Italiano Linfomi. ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned. N Engl J Med. 2011;365(3):203–212.

12 Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 2012;30(18):2183–2189.

13 Younes A, Connors JM, Park SI, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol. 2013;14(13):1348–1356.

14 Gordon LI, Hong F, Fisher RI, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013;31(6):684–691.

15 Borchmann P, Eichenauer DA, Plütschow A, et al. Targeted BEACOPP variants in patients with newly diagnosed advanced stage classical Hodgkin lymphoma: interim results of a randomized phase II study. Blood. 2013;122(21)4344.

16 Moskowitz CH, Nadamanee A, Masszi T, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2015;385(9980):1853–1862.

17 Evens AM, Helenowski I, Ramsdale E, et al. A retrospective multicenter analysis of elderly Hodgkin lymphoma: outcomes and prognostic factors in the modern era. Blood. 2012;119(3):692–695. 

18 Evens AM, et al. Sequential brentuximab vedotin and AVD for older Hodgkin lymphoma patients: initial results from a phase 2 multicentre study. In:  Hematological Oncology – Special Issue: 13-ICML, 13th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano (Switzerland), 17–20 June, 2015. Abstract 89.

19 Chen RW, Palmer J, Siddiqi T, et al. Brentuximab vedotin as first line salvage therapy in relapsed/refractory HL. Poster presented at: 54th ASH Annual Meeting and Exposition; December 8–11, 2012; Atlanta, GA.

20 Moskowitz AJ, Schoder H, Yahalom J, et al. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncol. 2015;16(3):284–292.

21 Moskowitz AJ, Hamlin PA, Jr, Perales MA, et al. Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol. 2013;31(4):456–460.

On Thursday, Oct. 22, the American Academy of Psychiatry and the Law begins its 46th annual meeting in Fort Lauderdale, Fla. Covering a myriad of topics related to both civil and criminal issues, each year a diverse group of international forensic psychiatrists meet to share experiences and stay current with emerging developments.

For the first time, the academy (also known as AAPL or “Apple”) will share this experience with the world. Using a mobile live streaming technology known as Meerkat, viewers will be able to watch presentations by panels of renowned forensic psychiatrists ranging from a presidential address entitled “Witness Protection Program: A Matter of Training,” on Thursday morning, to a panel discussion of the role of forensic psychiatry in the death penalty on Sunday morning. Viewers also will be able to take part in the discussion and ask questions live, either through Meerkat or Twitter.

To take part, download the Meerkat app from your respective app store. It’s free, and there are versions for both iPhone and Android. Log in with either Facebook or Twitter, then search for the AAPL stream “AAPL2015.” Volunteers at the presentation will be monitoring Meerkat interactions and accepting questions. Discussion also will take place on Twitter using the hashtag #AAPL2015 and a session-specific tag announced at the beginning of the presentation.

This year, one theme of the conference is medical education and, specifically, innovative ways to teach forensic psychiatry to general psychiatry residents and fellows. The use of social media at this conference is one example of this. Given that many residency programs do not have a board-certified forensic psychiatrist on faculty, remote viewing of lectures and conferences might be one solution for programs that are having difficulty meeting this Accreditation Council for Graduate Medical Education–required training content.

A full schedule of planned broadcasts, along with the approximate broadcast times, is available on the AAPL conference web page.

Here is a sample of some of the panel topics:

• The New APA Guidelines on Correctional Psychiatry

• The Psychiatrist in Peril: Current Topics in Malpractice

• Novel Approach to Teaching Residents About Violence and Safety

• The Relationship Between Mental Illness and Violence

• Adolescents and Social Media: Privacy, Brain Development, and Law

• Treatment of Transgender Inmates

• Educational Factors Contributing to Juvenile Delinquency

• Role of Forensic Psychiatry in Veteran Evaluations

• Myths and Realities of Women in Prison

• What Gets Judges in Trouble?

• Forensic Issues in Emergency Psychiatry

• TBI Update: International Collaboration on mTBI and DSM-5

• Forensic Psychiatry and the Death Penalty

• Rock and a Hard Place: Debating Sexual Sadism Diagnosis

Some psychiatry residents might imagine forensic psychiatry to be merely the provision of expert testimony, so I hope this conference expands that image to include the entire spectrum of potential forensic practice. AAPL traditionally has supported ready access to training in forensic psychiatry. Its affiliated quarterly publication, the Journal of the American Academy of Psychiatry and the Law, is one of the few peer-reviewed academic medical journals to remain free and open to the public. This publication contains scholarly articles dealing with the theory and practice of forensic psychiatry and related fields. In addition, the AAPL newsletter regularly provides updates of recent significant legal cases pertinent to the practice of psychiatry and updates on important legislative issues. Our members, through the APA’s Council on Psychiatry and Law, have helped the American Psychiatric Association address important issues related to mental health law and national policy involving psychiatric patients.

On behalf of the organization I would like to extend a welcome to our viewers and the general public: “Hello world!”

Dr. Hanson is a forensic psychiatrist and coauthor of Shrink Rap: Three Psychiatrists Explain Their Work. The opinions expressed are those of the author only and do not represent those of any of Dr. Hanson’s employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

On Thursday, Oct. 22, the American Academy of Psychiatry and the Law begins its 46th annual meeting in Fort Lauderdale, Fla. Covering a myriad of topics related to both civil and criminal issues, each year a diverse group of international forensic psychiatrists meet to share experiences and stay current with emerging developments.

For the first time, the academy (also known as AAPL or “Apple”) will share this experience with the world. Using a mobile live streaming technology known as Meerkat, viewers will be able to watch presentations by panels of renowned forensic psychiatrists ranging from a presidential address entitled “Witness Protection Program: A Matter of Training,” on Thursday morning, to a panel discussion of the role of forensic psychiatry in the death penalty on Sunday morning. Viewers also will be able to take part in the discussion and ask questions live, either through Meerkat or Twitter.

To take part, download the Meerkat app from your respective app store. It’s free, and there are versions for both iPhone and Android. Log in with either Facebook or Twitter, then search for the AAPL stream “AAPL2015.” Volunteers at the presentation will be monitoring Meerkat interactions and accepting questions. Discussion also will take place on Twitter using the hashtag #AAPL2015 and a session-specific tag announced at the beginning of the presentation.

This year, one theme of the conference is medical education and, specifically, innovative ways to teach forensic psychiatry to general psychiatry residents and fellows. The use of social media at this conference is one example of this. Given that many residency programs do not have a board-certified forensic psychiatrist on faculty, remote viewing of lectures and conferences might be one solution for programs that are having difficulty meeting this Accreditation Council for Graduate Medical Education–required training content.

A full schedule of planned broadcasts, along with the approximate broadcast times, is available on the AAPL conference web page.

Here is a sample of some of the panel topics:

• The New APA Guidelines on Correctional Psychiatry

• The Psychiatrist in Peril: Current Topics in Malpractice

• Novel Approach to Teaching Residents About Violence and Safety

• The Relationship Between Mental Illness and Violence

• Adolescents and Social Media: Privacy, Brain Development, and Law

• Treatment of Transgender Inmates

• Educational Factors Contributing to Juvenile Delinquency

• Role of Forensic Psychiatry in Veteran Evaluations

• Myths and Realities of Women in Prison

• What Gets Judges in Trouble?

• Forensic Issues in Emergency Psychiatry

• TBI Update: International Collaboration on mTBI and DSM-5

• Forensic Psychiatry and the Death Penalty

• Rock and a Hard Place: Debating Sexual Sadism Diagnosis

Some psychiatry residents might imagine forensic psychiatry to be merely the provision of expert testimony, so I hope this conference expands that image to include the entire spectrum of potential forensic practice. AAPL traditionally has supported ready access to training in forensic psychiatry. Its affiliated quarterly publication, the Journal of the American Academy of Psychiatry and the Law, is one of the few peer-reviewed academic medical journals to remain free and open to the public. This publication contains scholarly articles dealing with the theory and practice of forensic psychiatry and related fields. In addition, the AAPL newsletter regularly provides updates of recent significant legal cases pertinent to the practice of psychiatry and updates on important legislative issues. Our members, through the APA’s Council on Psychiatry and Law, have helped the American Psychiatric Association address important issues related to mental health law and national policy involving psychiatric patients.

On behalf of the organization I would like to extend a welcome to our viewers and the general public: “Hello world!”

Dr. Hanson is a forensic psychiatrist and coauthor of Shrink Rap: Three Psychiatrists Explain Their Work. The opinions expressed are those of the author only and do not represent those of any of Dr. Hanson’s employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

On Thursday, Oct. 22, the American Academy of Psychiatry and the Law begins its 46th annual meeting in Fort Lauderdale, Fla. Covering a myriad of topics related to both civil and criminal issues, each year a diverse group of international forensic psychiatrists meet to share experiences and stay current with emerging developments.

For the first time, the academy (also known as AAPL or “Apple”) will share this experience with the world. Using a mobile live streaming technology known as Meerkat, viewers will be able to watch presentations by panels of renowned forensic psychiatrists ranging from a presidential address entitled “Witness Protection Program: A Matter of Training,” on Thursday morning, to a panel discussion of the role of forensic psychiatry in the death penalty on Sunday morning. Viewers also will be able to take part in the discussion and ask questions live, either through Meerkat or Twitter.

To take part, download the Meerkat app from your respective app store. It’s free, and there are versions for both iPhone and Android. Log in with either Facebook or Twitter, then search for the AAPL stream “AAPL2015.” Volunteers at the presentation will be monitoring Meerkat interactions and accepting questions. Discussion also will take place on Twitter using the hashtag #AAPL2015 and a session-specific tag announced at the beginning of the presentation.

This year, one theme of the conference is medical education and, specifically, innovative ways to teach forensic psychiatry to general psychiatry residents and fellows. The use of social media at this conference is one example of this. Given that many residency programs do not have a board-certified forensic psychiatrist on faculty, remote viewing of lectures and conferences might be one solution for programs that are having difficulty meeting this Accreditation Council for Graduate Medical Education–required training content.

A full schedule of planned broadcasts, along with the approximate broadcast times, is available on the AAPL conference web page.

Here is a sample of some of the panel topics:

• The New APA Guidelines on Correctional Psychiatry

• The Psychiatrist in Peril: Current Topics in Malpractice

• Novel Approach to Teaching Residents About Violence and Safety

• The Relationship Between Mental Illness and Violence

• Adolescents and Social Media: Privacy, Brain Development, and Law

• Treatment of Transgender Inmates

• Educational Factors Contributing to Juvenile Delinquency

• Role of Forensic Psychiatry in Veteran Evaluations

• Myths and Realities of Women in Prison

• What Gets Judges in Trouble?

• Forensic Issues in Emergency Psychiatry

• TBI Update: International Collaboration on mTBI and DSM-5

• Forensic Psychiatry and the Death Penalty

• Rock and a Hard Place: Debating Sexual Sadism Diagnosis

Some psychiatry residents might imagine forensic psychiatry to be merely the provision of expert testimony, so I hope this conference expands that image to include the entire spectrum of potential forensic practice. AAPL traditionally has supported ready access to training in forensic psychiatry. Its affiliated quarterly publication, the Journal of the American Academy of Psychiatry and the Law, is one of the few peer-reviewed academic medical journals to remain free and open to the public. This publication contains scholarly articles dealing with the theory and practice of forensic psychiatry and related fields. In addition, the AAPL newsletter regularly provides updates of recent significant legal cases pertinent to the practice of psychiatry and updates on important legislative issues. Our members, through the APA’s Council on Psychiatry and Law, have helped the American Psychiatric Association address important issues related to mental health law and national policy involving psychiatric patients.

On behalf of the organization I would like to extend a welcome to our viewers and the general public: “Hello world!”

Dr. Hanson is a forensic psychiatrist and coauthor of Shrink Rap: Three Psychiatrists Explain Their Work. The opinions expressed are those of the author only and do not represent those of any of Dr. Hanson’s employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

Recently, Niam Yaraghi of the Brookings Institution caused quite a kerfuffle regarding the validity of online doctor reviews in a U.S. News and World Report op-ed piece titled, “Don’t Yelp Your Doctor.”

In it, he argues that customers are “generally qualified and capable” of reviewing a restaurant – anyone can tell if a steak is chewy or a server is rude, he says. (Of course, chefs may disagree.) Yet, when it comes to online physician reviews, Mr. Yaraghi argues that “patients are neither qualified nor capable of evaluating the quality of the medical services that they receive.” I can see many of you nodding in vigorous agreement with that last sentence.

Who among us hasn’t felt indignant after reading a negative online review? Particularly one that criticizes our office decor or billing, yet makes no mention of our expert clinical abilities? But here’s my advice. Have your moment of indignation, then start working on improving your online reputation, which may improve your actual practice as well.

Here are a few tips for optimizing online physician review sites:

• Google yourself and your practice to see which sites your patients are commonly using.

• Set up a Google Alert at https://www.google.com/alerts. Google Alerts are email updates that you receive based on your queries. Include your name and the name of your practice. This way, you’ll receive notice when you’re mentioned online.

• According to SoftwareAdvice.com, the most trusted review sites in descending order are: Yelp and Healthgrades (tied), RateMDs, Vitals, ZocDoc, and others. So familiarize yourself with these sites.

• Claim your page on review sites. Be sure all of the information listed is updated and correct.

• Upload a professional photo of yourself. It’s much more effective to see a picture of you than an empty avatar.

• Be sure someone in your office is responsible for responding to comments online, particularly negative ones. It’s best to respond promptly rather than have it linger without a response for weeks. If you don’t write it, then at least approve it before it is posted.

• Respond to both positive and negative comments. Yelp, for instance, rewards business owners who maintain their site and actively respond to comments.

• For specific tips on how to respond to negative online reviews, see my column from July 2013 titled “How to handle negative reviews.”

When it comes to online physician reviews, I want you to remember a few things:

• Physician reviews are usually favorable.

• Negative reviews are sometimes opportunities to improve your service.

• In the long run, we should want more, not fewer, reviews. Which would you rather have, two negative reviews, or two negative reviews and eight positive ones?

• The more reviews you have, the more credible you appear to prospective patients. This is particularly true for cosmetic practices.

• Patients are more likely to leave a positive review when they see other positive reviews posted about you.

Let’s delve more deeply into the second point, “Negative reviews are opportunities for you and your staff to improve your service.”

According to the 2014 “IndustryView report” from Software Advice, when it came to administrative issues such as wait times, billing, and staff friendliness, 25% of respondents cited wait times as the most important factor in their experience. Moreover, their 2013 report found that 41% of patients said they would consider switching doctors if it reduced their wait times

We live in a consumer-centric society and service matters. For most patients, service equals quality. If you’ve got multiple negative reviews regarding your front desk staff, for instance, then address it directly with them. If you’ve got complaints about long wait times, then consider ways to improve it or improve the patient’s experience of waiting. You might hire a consultant to help with reducing wait times or you might provide Wi-Fi or light refreshments in your waiting room to make the wait more pleasant.

Let’s return to Mr. Yaraghi’s contention that patients are unqualified to accurately assess our abilities. It is a moot discussion. Patients have, and will continue, evaluating us regardless of how qualified they are to do so. A restaurant patron may not be an expert of sous-vide cooking but can judge his or her experience of the meal and restaurant staff. Similarly, a patient may not be an expert in psoriasis, but he or she can accurately assess an experience in our office and with our staff.

The good news is that there are sites that are trying to incorporate more objective data in the reviews. For instance, Healthgrades lists doctors’ board certifications, hospital affiliations, conditions treated, and procedures performed. The hope is that more objective criteria will improve the quality of the reviews and make the occasional angry and unwarranted rant less important.

One thing is for sure, there is much more discussion to come.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego, and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

Recently, Niam Yaraghi of the Brookings Institution caused quite a kerfuffle regarding the validity of online doctor reviews in a U.S. News and World Report op-ed piece titled, “Don’t Yelp Your Doctor.”

In it, he argues that customers are “generally qualified and capable” of reviewing a restaurant – anyone can tell if a steak is chewy or a server is rude, he says. (Of course, chefs may disagree.) Yet, when it comes to online physician reviews, Mr. Yaraghi argues that “patients are neither qualified nor capable of evaluating the quality of the medical services that they receive.” I can see many of you nodding in vigorous agreement with that last sentence.

Who among us hasn’t felt indignant after reading a negative online review? Particularly one that criticizes our office decor or billing, yet makes no mention of our expert clinical abilities? But here’s my advice. Have your moment of indignation, then start working on improving your online reputation, which may improve your actual practice as well.

Here are a few tips for optimizing online physician review sites:

• Google yourself and your practice to see which sites your patients are commonly using.

• Set up a Google Alert at https://www.google.com/alerts. Google Alerts are email updates that you receive based on your queries. Include your name and the name of your practice. This way, you’ll receive notice when you’re mentioned online.

• According to SoftwareAdvice.com, the most trusted review sites in descending order are: Yelp and Healthgrades (tied), RateMDs, Vitals, ZocDoc, and others. So familiarize yourself with these sites.

• Claim your page on review sites. Be sure all of the information listed is updated and correct.

• Upload a professional photo of yourself. It’s much more effective to see a picture of you than an empty avatar.

• Be sure someone in your office is responsible for responding to comments online, particularly negative ones. It’s best to respond promptly rather than have it linger without a response for weeks. If you don’t write it, then at least approve it before it is posted.

• Respond to both positive and negative comments. Yelp, for instance, rewards business owners who maintain their site and actively respond to comments.

• For specific tips on how to respond to negative online reviews, see my column from July 2013 titled “How to handle negative reviews.”

When it comes to online physician reviews, I want you to remember a few things:

• Physician reviews are usually favorable.

• Negative reviews are sometimes opportunities to improve your service.

• In the long run, we should want more, not fewer, reviews. Which would you rather have, two negative reviews, or two negative reviews and eight positive ones?

• The more reviews you have, the more credible you appear to prospective patients. This is particularly true for cosmetic practices.

• Patients are more likely to leave a positive review when they see other positive reviews posted about you.

Let’s delve more deeply into the second point, “Negative reviews are opportunities for you and your staff to improve your service.”

According to the 2014 “IndustryView report” from Software Advice, when it came to administrative issues such as wait times, billing, and staff friendliness, 25% of respondents cited wait times as the most important factor in their experience. Moreover, their 2013 report found that 41% of patients said they would consider switching doctors if it reduced their wait times

We live in a consumer-centric society and service matters. For most patients, service equals quality. If you’ve got multiple negative reviews regarding your front desk staff, for instance, then address it directly with them. If you’ve got complaints about long wait times, then consider ways to improve it or improve the patient’s experience of waiting. You might hire a consultant to help with reducing wait times or you might provide Wi-Fi or light refreshments in your waiting room to make the wait more pleasant.

Let’s return to Mr. Yaraghi’s contention that patients are unqualified to accurately assess our abilities. It is a moot discussion. Patients have, and will continue, evaluating us regardless of how qualified they are to do so. A restaurant patron may not be an expert of sous-vide cooking but can judge his or her experience of the meal and restaurant staff. Similarly, a patient may not be an expert in psoriasis, but he or she can accurately assess an experience in our office and with our staff.

The good news is that there are sites that are trying to incorporate more objective data in the reviews. For instance, Healthgrades lists doctors’ board certifications, hospital affiliations, conditions treated, and procedures performed. The hope is that more objective criteria will improve the quality of the reviews and make the occasional angry and unwarranted rant less important.

One thing is for sure, there is much more discussion to come.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego, and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

Recently, Niam Yaraghi of the Brookings Institution caused quite a kerfuffle regarding the validity of online doctor reviews in a U.S. News and World Report op-ed piece titled, “Don’t Yelp Your Doctor.”

In it, he argues that customers are “generally qualified and capable” of reviewing a restaurant – anyone can tell if a steak is chewy or a server is rude, he says. (Of course, chefs may disagree.) Yet, when it comes to online physician reviews, Mr. Yaraghi argues that “patients are neither qualified nor capable of evaluating the quality of the medical services that they receive.” I can see many of you nodding in vigorous agreement with that last sentence.

Who among us hasn’t felt indignant after reading a negative online review? Particularly one that criticizes our office decor or billing, yet makes no mention of our expert clinical abilities? But here’s my advice. Have your moment of indignation, then start working on improving your online reputation, which may improve your actual practice as well.

Here are a few tips for optimizing online physician review sites:

• Google yourself and your practice to see which sites your patients are commonly using.

• Set up a Google Alert at https://www.google.com/alerts. Google Alerts are email updates that you receive based on your queries. Include your name and the name of your practice. This way, you’ll receive notice when you’re mentioned online.

• According to SoftwareAdvice.com, the most trusted review sites in descending order are: Yelp and Healthgrades (tied), RateMDs, Vitals, ZocDoc, and others. So familiarize yourself with these sites.

• Claim your page on review sites. Be sure all of the information listed is updated and correct.

• Upload a professional photo of yourself. It’s much more effective to see a picture of you than an empty avatar.

• Be sure someone in your office is responsible for responding to comments online, particularly negative ones. It’s best to respond promptly rather than have it linger without a response for weeks. If you don’t write it, then at least approve it before it is posted.

• Respond to both positive and negative comments. Yelp, for instance, rewards business owners who maintain their site and actively respond to comments.

• For specific tips on how to respond to negative online reviews, see my column from July 2013 titled “How to handle negative reviews.”

When it comes to online physician reviews, I want you to remember a few things:

• Physician reviews are usually favorable.

• Negative reviews are sometimes opportunities to improve your service.

• In the long run, we should want more, not fewer, reviews. Which would you rather have, two negative reviews, or two negative reviews and eight positive ones?

• The more reviews you have, the more credible you appear to prospective patients. This is particularly true for cosmetic practices.

• Patients are more likely to leave a positive review when they see other positive reviews posted about you.

Let’s delve more deeply into the second point, “Negative reviews are opportunities for you and your staff to improve your service.”

According to the 2014 “IndustryView report” from Software Advice, when it came to administrative issues such as wait times, billing, and staff friendliness, 25% of respondents cited wait times as the most important factor in their experience. Moreover, their 2013 report found that 41% of patients said they would consider switching doctors if it reduced their wait times

We live in a consumer-centric society and service matters. For most patients, service equals quality. If you’ve got multiple negative reviews regarding your front desk staff, for instance, then address it directly with them. If you’ve got complaints about long wait times, then consider ways to improve it or improve the patient’s experience of waiting. You might hire a consultant to help with reducing wait times or you might provide Wi-Fi or light refreshments in your waiting room to make the wait more pleasant.

Let’s return to Mr. Yaraghi’s contention that patients are unqualified to accurately assess our abilities. It is a moot discussion. Patients have, and will continue, evaluating us regardless of how qualified they are to do so. A restaurant patron may not be an expert of sous-vide cooking but can judge his or her experience of the meal and restaurant staff. Similarly, a patient may not be an expert in psoriasis, but he or she can accurately assess an experience in our office and with our staff.

The good news is that there are sites that are trying to incorporate more objective data in the reviews. For instance, Healthgrades lists doctors’ board certifications, hospital affiliations, conditions treated, and procedures performed. The hope is that more objective criteria will improve the quality of the reviews and make the occasional angry and unwarranted rant less important.

One thing is for sure, there is much more discussion to come.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego, and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.