Hodgkin Lymphoma

Pembrolizumab treatment significantly improved progression-free survival versus brentuximab vedotin in a randomized, phase 3 trial including patients with relapsed or refractory classical Hodgkin lymphoma, an investigator has reported.

Median progression-free survival (PFS) was 13.2 versus 8.3 months in favor of pembrolizumab, according to the report on the KEYNOTE-204 trial, which included patients with classical Hodgkin lymphoma who either had relapsed after autologous stem cell transplant (SCT) or were ineligible for autologous SCT.

The PFS improvement was “statistically significant and clinically meaningful,” said investigator John Kuruvilla, MD, of Princess Margaret Cancer Centre in Toronto.

“This PFS benefit extended to key subgroups, including those ineligible for autologous transplant, patients with primary refractory disease, and patients who were brentuximab-vedotin naive,” Dr. Kuruvilla added in his presentation, which was part of the American Society of Clinical Oncology virtual scientific program.

Pneumonitis was more frequent in the pembrolizumab arm, but “appeared in general to be quite well managed” among patients who experienced this adverse event, according to Dr. Kuruvilla, who said that treatment with the programmed death–1 inhibitor should be considered “the preferred treatment option and the new standard of care” for patients with relapsed/refractory classic Hodgkin lymphoma who have relapsed after autologous SCT or are ineligible for it.

Although the pneumonitis findings are important to keep in mind, results of KEYNOTE-204 are indeed “practice defining” and immediately impactful, said Mark J. Roschewski, MD, clinical investigator in the lymphoid malignancies branch at the Center for Cancer Research, part of the National Cancer Institute, Bethesda, Md.

“I would select pembrolizumab over brentuximab for this patient population, particularly those that are refractory to chemotherapy,” he said in a commentary on the study also included in the virtual ASCO proceedings.

“There may be specific patient populations that I’d reconsider, such as those that might be at high risk for lung toxicity,” he added. “They may not be suitable for this, but it’s something to at least to be aware of.”

Although the antibody-drug conjugate brentuximab vedotin has been considered the standard of care for patients with relapse after autologous SCT, there has historically been no standard of care for patients who are ineligible for transplant because of chemorefractory disease, advanced age, or comorbidities, Dr. Kuruvilla said in his presentation.

In the KEYNOTE-204 study, 304 patients with relapsed/refractory classic Hodgkin lymphoma were randomized to receive either pembrolizumab 200 mg or brentuximab at 1.8 mg/kg intravenously every 3 weeks for up to 35 cycles.

The median age of patients was 36 years in the pembrolizumab arm and 35 years in the brentuximab vedotin arm, according to the report. Approximately 37% of the patients had previously undergone autologous SCT. About 40% had been refractory to frontline therapy, while 28% relapsed within 12 months of therapy and 32% relapsed later than 12 months.

Median PFS by blinded independent central review was 13.2 versus 8.3 months in the pembrolizumab and brentuximab arms, respectively (hazard ratio, 0.65; 95% confidence interval, 0.48-0.88; P = .00271), Dr. Kuruvilla reported.

The benefit extended to “key subgroups” in the trial, he added, including those who were ineligible for autologous SCT, those with primary refractory disease, and those who were naive to brentuximab vedotin, with HRs of 0.61, 0.52, and 0.67, respectively.

Pembrolizumab was also associated with more durable responses versus brentuximab vedotin, according to the investigator.

The overall response rate was 65.6% and 54.2%, respectively, for pembrolizumab and brentuximab, although this difference of approximately 11 percentage points did not meet criteria for statistical significance, he said. Duration of response was 20.7 months or pembrolizumab and 13.8 months for brentuximab.

The rate of serious treatment-related adverse events was similar between groups, according to Dr. Kuruvilla, who reported grade 3-5 events occurring in 19.6% and 25.0% of the pembrolizumab and brentuximab arms. Serious treatment-related adverse events were numerically more frequent in the pembrolizumab arm (16.2% vs. 10.5%) and there was one treatment-related death caused by pneumonia, seen in the pembrolizumab arm.

Pneumonitis occurred in 2.6% of the brentuximab-treated patients and in 10.8% of pembrolizumab-treated patients, of which half of cases were grade 3-4, according to the report.

In the pembrolizumab arm, pneumonitis was felt to be drug-related in 15 of 16 cases, according to Dr. Kuruvilla, who added that 15 of 16 patients required corticosteroid therapy. “This has led to the resolution of the pneumonitis in 12 of 16 patients, with ongoing resolution in one further patient.”

Research funding for KEYNOTE-204 came from Merck Sharp & Dohme. Dr. Kuruvilla provided disclosures related to Merck and a variety of other pharmaceutical companies. Dr. Roschewski said he had no relationships to disclose.

SOURCE: Kuruvilla J et al. ASCO 2020, Abstract 8005.

Pembrolizumab treatment significantly improved progression-free survival versus brentuximab vedotin in a randomized, phase 3 trial including patients with relapsed or refractory classical Hodgkin lymphoma, an investigator has reported.

Median progression-free survival (PFS) was 13.2 versus 8.3 months in favor of pembrolizumab, according to the report on the KEYNOTE-204 trial, which included patients with classical Hodgkin lymphoma who either had relapsed after autologous stem cell transplant (SCT) or were ineligible for autologous SCT.

The PFS improvement was “statistically significant and clinically meaningful,” said investigator John Kuruvilla, MD, of Princess Margaret Cancer Centre in Toronto.

“This PFS benefit extended to key subgroups, including those ineligible for autologous transplant, patients with primary refractory disease, and patients who were brentuximab-vedotin naive,” Dr. Kuruvilla added in his presentation, which was part of the American Society of Clinical Oncology virtual scientific program.

Pneumonitis was more frequent in the pembrolizumab arm, but “appeared in general to be quite well managed” among patients who experienced this adverse event, according to Dr. Kuruvilla, who said that treatment with the programmed death–1 inhibitor should be considered “the preferred treatment option and the new standard of care” for patients with relapsed/refractory classic Hodgkin lymphoma who have relapsed after autologous SCT or are ineligible for it.

Although the pneumonitis findings are important to keep in mind, results of KEYNOTE-204 are indeed “practice defining” and immediately impactful, said Mark J. Roschewski, MD, clinical investigator in the lymphoid malignancies branch at the Center for Cancer Research, part of the National Cancer Institute, Bethesda, Md.

“I would select pembrolizumab over brentuximab for this patient population, particularly those that are refractory to chemotherapy,” he said in a commentary on the study also included in the virtual ASCO proceedings.

“There may be specific patient populations that I’d reconsider, such as those that might be at high risk for lung toxicity,” he added. “They may not be suitable for this, but it’s something to at least to be aware of.”

Although the antibody-drug conjugate brentuximab vedotin has been considered the standard of care for patients with relapse after autologous SCT, there has historically been no standard of care for patients who are ineligible for transplant because of chemorefractory disease, advanced age, or comorbidities, Dr. Kuruvilla said in his presentation.

In the KEYNOTE-204 study, 304 patients with relapsed/refractory classic Hodgkin lymphoma were randomized to receive either pembrolizumab 200 mg or brentuximab at 1.8 mg/kg intravenously every 3 weeks for up to 35 cycles.

The median age of patients was 36 years in the pembrolizumab arm and 35 years in the brentuximab vedotin arm, according to the report. Approximately 37% of the patients had previously undergone autologous SCT. About 40% had been refractory to frontline therapy, while 28% relapsed within 12 months of therapy and 32% relapsed later than 12 months.

Median PFS by blinded independent central review was 13.2 versus 8.3 months in the pembrolizumab and brentuximab arms, respectively (hazard ratio, 0.65; 95% confidence interval, 0.48-0.88; P = .00271), Dr. Kuruvilla reported.

The benefit extended to “key subgroups” in the trial, he added, including those who were ineligible for autologous SCT, those with primary refractory disease, and those who were naive to brentuximab vedotin, with HRs of 0.61, 0.52, and 0.67, respectively.

Pembrolizumab was also associated with more durable responses versus brentuximab vedotin, according to the investigator.

The overall response rate was 65.6% and 54.2%, respectively, for pembrolizumab and brentuximab, although this difference of approximately 11 percentage points did not meet criteria for statistical significance, he said. Duration of response was 20.7 months or pembrolizumab and 13.8 months for brentuximab.

The rate of serious treatment-related adverse events was similar between groups, according to Dr. Kuruvilla, who reported grade 3-5 events occurring in 19.6% and 25.0% of the pembrolizumab and brentuximab arms. Serious treatment-related adverse events were numerically more frequent in the pembrolizumab arm (16.2% vs. 10.5%) and there was one treatment-related death caused by pneumonia, seen in the pembrolizumab arm.

Pneumonitis occurred in 2.6% of the brentuximab-treated patients and in 10.8% of pembrolizumab-treated patients, of which half of cases were grade 3-4, according to the report.

In the pembrolizumab arm, pneumonitis was felt to be drug-related in 15 of 16 cases, according to Dr. Kuruvilla, who added that 15 of 16 patients required corticosteroid therapy. “This has led to the resolution of the pneumonitis in 12 of 16 patients, with ongoing resolution in one further patient.”

Research funding for KEYNOTE-204 came from Merck Sharp & Dohme. Dr. Kuruvilla provided disclosures related to Merck and a variety of other pharmaceutical companies. Dr. Roschewski said he had no relationships to disclose.

SOURCE: Kuruvilla J et al. ASCO 2020, Abstract 8005.

Pembrolizumab treatment significantly improved progression-free survival versus brentuximab vedotin in a randomized, phase 3 trial including patients with relapsed or refractory classical Hodgkin lymphoma, an investigator has reported.

Median progression-free survival (PFS) was 13.2 versus 8.3 months in favor of pembrolizumab, according to the report on the KEYNOTE-204 trial, which included patients with classical Hodgkin lymphoma who either had relapsed after autologous stem cell transplant (SCT) or were ineligible for autologous SCT.

The PFS improvement was “statistically significant and clinically meaningful,” said investigator John Kuruvilla, MD, of Princess Margaret Cancer Centre in Toronto.

“This PFS benefit extended to key subgroups, including those ineligible for autologous transplant, patients with primary refractory disease, and patients who were brentuximab-vedotin naive,” Dr. Kuruvilla added in his presentation, which was part of the American Society of Clinical Oncology virtual scientific program.

Pneumonitis was more frequent in the pembrolizumab arm, but “appeared in general to be quite well managed” among patients who experienced this adverse event, according to Dr. Kuruvilla, who said that treatment with the programmed death–1 inhibitor should be considered “the preferred treatment option and the new standard of care” for patients with relapsed/refractory classic Hodgkin lymphoma who have relapsed after autologous SCT or are ineligible for it.

Although the pneumonitis findings are important to keep in mind, results of KEYNOTE-204 are indeed “practice defining” and immediately impactful, said Mark J. Roschewski, MD, clinical investigator in the lymphoid malignancies branch at the Center for Cancer Research, part of the National Cancer Institute, Bethesda, Md.

“I would select pembrolizumab over brentuximab for this patient population, particularly those that are refractory to chemotherapy,” he said in a commentary on the study also included in the virtual ASCO proceedings.

“There may be specific patient populations that I’d reconsider, such as those that might be at high risk for lung toxicity,” he added. “They may not be suitable for this, but it’s something to at least to be aware of.”

Although the antibody-drug conjugate brentuximab vedotin has been considered the standard of care for patients with relapse after autologous SCT, there has historically been no standard of care for patients who are ineligible for transplant because of chemorefractory disease, advanced age, or comorbidities, Dr. Kuruvilla said in his presentation.

In the KEYNOTE-204 study, 304 patients with relapsed/refractory classic Hodgkin lymphoma were randomized to receive either pembrolizumab 200 mg or brentuximab at 1.8 mg/kg intravenously every 3 weeks for up to 35 cycles.

The median age of patients was 36 years in the pembrolizumab arm and 35 years in the brentuximab vedotin arm, according to the report. Approximately 37% of the patients had previously undergone autologous SCT. About 40% had been refractory to frontline therapy, while 28% relapsed within 12 months of therapy and 32% relapsed later than 12 months.

Median PFS by blinded independent central review was 13.2 versus 8.3 months in the pembrolizumab and brentuximab arms, respectively (hazard ratio, 0.65; 95% confidence interval, 0.48-0.88; P = .00271), Dr. Kuruvilla reported.

The benefit extended to “key subgroups” in the trial, he added, including those who were ineligible for autologous SCT, those with primary refractory disease, and those who were naive to brentuximab vedotin, with HRs of 0.61, 0.52, and 0.67, respectively.

Pembrolizumab was also associated with more durable responses versus brentuximab vedotin, according to the investigator.

The overall response rate was 65.6% and 54.2%, respectively, for pembrolizumab and brentuximab, although this difference of approximately 11 percentage points did not meet criteria for statistical significance, he said. Duration of response was 20.7 months or pembrolizumab and 13.8 months for brentuximab.

The rate of serious treatment-related adverse events was similar between groups, according to Dr. Kuruvilla, who reported grade 3-5 events occurring in 19.6% and 25.0% of the pembrolizumab and brentuximab arms. Serious treatment-related adverse events were numerically more frequent in the pembrolizumab arm (16.2% vs. 10.5%) and there was one treatment-related death caused by pneumonia, seen in the pembrolizumab arm.

Pneumonitis occurred in 2.6% of the brentuximab-treated patients and in 10.8% of pembrolizumab-treated patients, of which half of cases were grade 3-4, according to the report.

In the pembrolizumab arm, pneumonitis was felt to be drug-related in 15 of 16 cases, according to Dr. Kuruvilla, who added that 15 of 16 patients required corticosteroid therapy. “This has led to the resolution of the pneumonitis in 12 of 16 patients, with ongoing resolution in one further patient.”

Research funding for KEYNOTE-204 came from Merck Sharp & Dohme. Dr. Kuruvilla provided disclosures related to Merck and a variety of other pharmaceutical companies. Dr. Roschewski said he had no relationships to disclose.

SOURCE: Kuruvilla J et al. ASCO 2020, Abstract 8005.

Nearly one in five individuals with cancer who are treated with immune checkpoint inhibitors develop thyroid dysfunction, new research suggests.

Sebastian Kaulitzki/Fotolia

Immune checkpoint inhibitors have revolutionized the treatment of many different types of cancers, but can also trigger a variety of immune-related adverse effects. As these drugs become more widely used, rates of these events appear to be more common in the real-world compared with clinical trial settings.

In their new study, Zoe Quandt, MD, of the University of California, San Francisco (UCSF), and colleagues specifically looked at thyroid dysfunction in their own institution’s EHR data and found more than double the rate of hypothyroidism and more than triple the rate of hyperthyroidism, compared with rates in published trials.

Moreover, in contrast to previous studies that have found differences in thyroid dysfunction by checkpoint inhibitor type, Dr. Quandt and colleagues instead found significant differences by cancer type.

Dr. Quandt presented the findings during a virtual press briefing held March 31originally scheduled for ENDO 2020.

“Thyroid dysfunction following checkpoint inhibitor therapy appears to be much more common than was previously reported in clinical trials, and this is one of the first studies to show differences by cancer type rather than by checkpoint inhibitor type,” Dr. Quandt said during the presentation.

However, she also cautioned that there’s “a lot more research to be done to validate case definitions and validate these findings.”

Asked to comment, endocrinologist David C. Lieb, MD, associate professor of medicine at Eastern Virginia Medical School in Norfolk, said in an interview, “These drugs are becoming so much more commonly used, so it’s not surprising that we’re seeing more endocrine complications, especially thyroid disease.”

“Endocrinologists need to work closely with oncologists to make sure patients are being screened and followed appropriately.”

‘A much higher percentage than we were expecting’

Dr. Quandt’s study included 1,146 individuals treated with checkpoint inhibitors at UCSF during 2012-2018 who did not have thyroid cancer or preexisting thyroid dysfunction.

Pembrolizumab (Keytruda) was the most common treatment (45%), followed by nivolumab (Opdivo) (20%). Less than 10% of patients received atezolizumab (Tecentriq), durvalumab (Imfizi), ipilimumab (Yervoy) monotherapy, combined ipilimumab/nivolumab, or other combinations of checkpoint inhibitors.

A total of 19.1% developed thyroid disease, with 13.4% having hypothyroidism and 9.5% hyperthyroidism. These figures far exceed those found in a recent meta-analysis of 38 randomized clinical trials of checkpoint inhibitors that included 7551 patients.

“Using this approach, we found a much higher percentage of patients who developed thyroid dysfunction than we were expecting,” Dr. Quandt said.

In both cases, the two categories – hypothyroidism and hyperthyroidism – aren’t mutually exclusive as hypothyroidism can arise de novo or subsequent to hyperthyroidism.

Dr Lieb commented, “It would be interesting to see what the causes of hyperthyroidism are – thyroiditis or Graves disease.”

Dr. Quandt mentioned a possible reason for the large difference between clinical trial and real-world data.

“Once we’re actually using these drugs outside of clinical trials, some of the restrictions about using them in people with other autoimmune diseases have been lifted, so my guess is that as we give them to a broader population we’re seeing more of these [adverse effects],” she suggested.

Also, “In the initial trials, people weren’t quite as aware of the possibilities of these side effects, so now we’re doing many more labs. Patients get thyroid function tests with every infusion, so I think we’re probably catching more patients who develop disease.”
 

Differences by cancer type, not checkpoint inhibitor type

And in a new twist, Dr. Quandt found that, in contrast to the differences seen by checkpoint inhibitor type in randomized trials, “surprisingly, we found that this difference did not reach statistical significance.”

“Instead, we saw that cancer type was associated with development of thyroid dysfunction, even after taking checkpoint inhibitor type into account.”

The percentages of patients who developed thyroid dysfunction ranged from 9.7% of those with glioblastoma to 40.0% of those with renal cell carcinoma.

The reason for this is not clear, said Dr. Quandt in an interview.

One possibility relates to other treatments patients with cancer also receive. In renal cell carcinoma, for example, patients also are treated with tyrosine kinase inhibitors, which can also cause thyroid dysfunction, so they may be more susceptible. Or there may be shared antigens activating the immune system.

“That’s definitely one of the questions we’re looking at,” she said.

Dr. Quandt and Dr. Lieb have reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Nearly one in five individuals with cancer who are treated with immune checkpoint inhibitors develop thyroid dysfunction, new research suggests.

Sebastian Kaulitzki/Fotolia

Immune checkpoint inhibitors have revolutionized the treatment of many different types of cancers, but can also trigger a variety of immune-related adverse effects. As these drugs become more widely used, rates of these events appear to be more common in the real-world compared with clinical trial settings.

In their new study, Zoe Quandt, MD, of the University of California, San Francisco (UCSF), and colleagues specifically looked at thyroid dysfunction in their own institution’s EHR data and found more than double the rate of hypothyroidism and more than triple the rate of hyperthyroidism, compared with rates in published trials.

Moreover, in contrast to previous studies that have found differences in thyroid dysfunction by checkpoint inhibitor type, Dr. Quandt and colleagues instead found significant differences by cancer type.

Dr. Quandt presented the findings during a virtual press briefing held March 31originally scheduled for ENDO 2020.

“Thyroid dysfunction following checkpoint inhibitor therapy appears to be much more common than was previously reported in clinical trials, and this is one of the first studies to show differences by cancer type rather than by checkpoint inhibitor type,” Dr. Quandt said during the presentation.

However, she also cautioned that there’s “a lot more research to be done to validate case definitions and validate these findings.”

Asked to comment, endocrinologist David C. Lieb, MD, associate professor of medicine at Eastern Virginia Medical School in Norfolk, said in an interview, “These drugs are becoming so much more commonly used, so it’s not surprising that we’re seeing more endocrine complications, especially thyroid disease.”

“Endocrinologists need to work closely with oncologists to make sure patients are being screened and followed appropriately.”

‘A much higher percentage than we were expecting’

Dr. Quandt’s study included 1,146 individuals treated with checkpoint inhibitors at UCSF during 2012-2018 who did not have thyroid cancer or preexisting thyroid dysfunction.

Pembrolizumab (Keytruda) was the most common treatment (45%), followed by nivolumab (Opdivo) (20%). Less than 10% of patients received atezolizumab (Tecentriq), durvalumab (Imfizi), ipilimumab (Yervoy) monotherapy, combined ipilimumab/nivolumab, or other combinations of checkpoint inhibitors.

A total of 19.1% developed thyroid disease, with 13.4% having hypothyroidism and 9.5% hyperthyroidism. These figures far exceed those found in a recent meta-analysis of 38 randomized clinical trials of checkpoint inhibitors that included 7551 patients.

“Using this approach, we found a much higher percentage of patients who developed thyroid dysfunction than we were expecting,” Dr. Quandt said.

In both cases, the two categories – hypothyroidism and hyperthyroidism – aren’t mutually exclusive as hypothyroidism can arise de novo or subsequent to hyperthyroidism.

Dr Lieb commented, “It would be interesting to see what the causes of hyperthyroidism are – thyroiditis or Graves disease.”

Dr. Quandt mentioned a possible reason for the large difference between clinical trial and real-world data.

“Once we’re actually using these drugs outside of clinical trials, some of the restrictions about using them in people with other autoimmune diseases have been lifted, so my guess is that as we give them to a broader population we’re seeing more of these [adverse effects],” she suggested.

Also, “In the initial trials, people weren’t quite as aware of the possibilities of these side effects, so now we’re doing many more labs. Patients get thyroid function tests with every infusion, so I think we’re probably catching more patients who develop disease.”
 

Differences by cancer type, not checkpoint inhibitor type

And in a new twist, Dr. Quandt found that, in contrast to the differences seen by checkpoint inhibitor type in randomized trials, “surprisingly, we found that this difference did not reach statistical significance.”

“Instead, we saw that cancer type was associated with development of thyroid dysfunction, even after taking checkpoint inhibitor type into account.”

The percentages of patients who developed thyroid dysfunction ranged from 9.7% of those with glioblastoma to 40.0% of those with renal cell carcinoma.

The reason for this is not clear, said Dr. Quandt in an interview.

One possibility relates to other treatments patients with cancer also receive. In renal cell carcinoma, for example, patients also are treated with tyrosine kinase inhibitors, which can also cause thyroid dysfunction, so they may be more susceptible. Or there may be shared antigens activating the immune system.

“That’s definitely one of the questions we’re looking at,” she said.

Dr. Quandt and Dr. Lieb have reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Nearly one in five individuals with cancer who are treated with immune checkpoint inhibitors develop thyroid dysfunction, new research suggests.

Sebastian Kaulitzki/Fotolia

Immune checkpoint inhibitors have revolutionized the treatment of many different types of cancers, but can also trigger a variety of immune-related adverse effects. As these drugs become more widely used, rates of these events appear to be more common in the real-world compared with clinical trial settings.

In their new study, Zoe Quandt, MD, of the University of California, San Francisco (UCSF), and colleagues specifically looked at thyroid dysfunction in their own institution’s EHR data and found more than double the rate of hypothyroidism and more than triple the rate of hyperthyroidism, compared with rates in published trials.

Moreover, in contrast to previous studies that have found differences in thyroid dysfunction by checkpoint inhibitor type, Dr. Quandt and colleagues instead found significant differences by cancer type.

Dr. Quandt presented the findings during a virtual press briefing held March 31originally scheduled for ENDO 2020.

“Thyroid dysfunction following checkpoint inhibitor therapy appears to be much more common than was previously reported in clinical trials, and this is one of the first studies to show differences by cancer type rather than by checkpoint inhibitor type,” Dr. Quandt said during the presentation.

However, she also cautioned that there’s “a lot more research to be done to validate case definitions and validate these findings.”

Asked to comment, endocrinologist David C. Lieb, MD, associate professor of medicine at Eastern Virginia Medical School in Norfolk, said in an interview, “These drugs are becoming so much more commonly used, so it’s not surprising that we’re seeing more endocrine complications, especially thyroid disease.”

“Endocrinologists need to work closely with oncologists to make sure patients are being screened and followed appropriately.”

‘A much higher percentage than we were expecting’

Dr. Quandt’s study included 1,146 individuals treated with checkpoint inhibitors at UCSF during 2012-2018 who did not have thyroid cancer or preexisting thyroid dysfunction.

Pembrolizumab (Keytruda) was the most common treatment (45%), followed by nivolumab (Opdivo) (20%). Less than 10% of patients received atezolizumab (Tecentriq), durvalumab (Imfizi), ipilimumab (Yervoy) monotherapy, combined ipilimumab/nivolumab, or other combinations of checkpoint inhibitors.

A total of 19.1% developed thyroid disease, with 13.4% having hypothyroidism and 9.5% hyperthyroidism. These figures far exceed those found in a recent meta-analysis of 38 randomized clinical trials of checkpoint inhibitors that included 7551 patients.

“Using this approach, we found a much higher percentage of patients who developed thyroid dysfunction than we were expecting,” Dr. Quandt said.

In both cases, the two categories – hypothyroidism and hyperthyroidism – aren’t mutually exclusive as hypothyroidism can arise de novo or subsequent to hyperthyroidism.

Dr Lieb commented, “It would be interesting to see what the causes of hyperthyroidism are – thyroiditis or Graves disease.”

Dr. Quandt mentioned a possible reason for the large difference between clinical trial and real-world data.

“Once we’re actually using these drugs outside of clinical trials, some of the restrictions about using them in people with other autoimmune diseases have been lifted, so my guess is that as we give them to a broader population we’re seeing more of these [adverse effects],” she suggested.

Also, “In the initial trials, people weren’t quite as aware of the possibilities of these side effects, so now we’re doing many more labs. Patients get thyroid function tests with every infusion, so I think we’re probably catching more patients who develop disease.”
 

Differences by cancer type, not checkpoint inhibitor type

And in a new twist, Dr. Quandt found that, in contrast to the differences seen by checkpoint inhibitor type in randomized trials, “surprisingly, we found that this difference did not reach statistical significance.”

“Instead, we saw that cancer type was associated with development of thyroid dysfunction, even after taking checkpoint inhibitor type into account.”

The percentages of patients who developed thyroid dysfunction ranged from 9.7% of those with glioblastoma to 40.0% of those with renal cell carcinoma.

The reason for this is not clear, said Dr. Quandt in an interview.

One possibility relates to other treatments patients with cancer also receive. In renal cell carcinoma, for example, patients also are treated with tyrosine kinase inhibitors, which can also cause thyroid dysfunction, so they may be more susceptible. Or there may be shared antigens activating the immune system.

“That’s definitely one of the questions we’re looking at,” she said.

Dr. Quandt and Dr. Lieb have reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

A patient with HIV remission induced by stem cell transplantation continues to be disease free at the 30-month mark.

The individual, referred to as the London patient, received allogeneic hematopoietic stem cell transplantation (allo-HSCT) for stage IVB Hodgkin lymphoma. The transplant donor was homozygous for the CCR5 delta-32 mutation, which confers immunity to HIV because there’s no point of entry for the virus into immune cells.

After extensive sampling of various tissues, including gut, lymph node, blood, semen, and cerebrospinal fluid (CSF), Ravindra Kumar Gupta, MD, PhD, and colleagues found no detectable virus that was competent to replicate. However, they reported that the testing did detect some “fossilized” remnants of HIV DNA persisting in certain tissues.

The results were shared in a video presentation of the research during the Conference on Retroviruses & Opportunistic Infections, which was presented online this year. CROI organizers chose to hold a virtual meeting because of concerns about the spread of COVID-19.

The London patient’s HIV status had been reported the previous year at CROI 2019, but only blood samples were used in that analysis.

In a commentary accompanying the simultaneously published study in the Lancet, Jennifer Zerbato, PhD, and Sharon Lewin, FRACP, PHD, FAAHMS, asked: “A key question now for the area of HIV cure is how soon can one know if someone has been cured of HIV?

“We will need more than a handful of patients cured of HIV to really understand the duration of follow-up needed and the likelihood of an unexpected late rebound in virus replication,” continued Dr. Zerbato, of the University of Melbourne, and Dr. Lewin, of the Royal Melbourne Hospital and Monash University, also in Melbourne.

In their ongoing analysis of data from the London patient, Dr. Gupta, a virologist at the University of Cambridge (England), and associates constructed a mathematical model that maps the probability for lifetime remission or cure of HIV against several factors, including the degree of chimerism achieved with the stem cell transplant.

In this model, when chimerism reaches 80% in total HIV target cells, the probability of remission for life is 98%; when donor chimerism reaches 90%, the probability of lifetime remission is greater than 99%. Peripheral T-cell chimerism in the London patient has held steady at 99%.

Dr. Gupta and associates obtained some testing opportunistically: A PET-CT scan revealed an axillary lymph node that was biopsied after it was found to have avid radiotracer uptake. Similarly, the CSF sample was obtained in the course of a work-up for some neurologic symptoms that the London patient was having.

In contrast to the first patient who achieved ongoing HIV remission from a pair of stem cell transplants received over 13 years ago – the Berlin patient – the London patient did not receive whole-body radiation, but rather underwent a reduced-intensity conditioning regimen. The London patient experienced a bout of gut graft-versus-host disease (GVHD) about 2 months after his transplant, but has been free of GVHD in the interval. He hasn’t taken cytotoxic agents or any GVHD prophylaxis since 6 months post transplant.

Though there’s no sign of HIV that’s competent to replicate, “the London patient has shown somewhat slow CD4 reconstitution,” said Dr. Gupta and coauthors in discussing the results.

The patient had a reactivation of Epstein-Barr virus (EBV) about 21 months after analytic treatment interruption (ATI) of antiretroviral therapy that was managed without any specific treatment, but he hasn’t experienced any opportunistic infections. However, his CD4 count didn’t rebound to pretransplant levels until 28 months after ATI. At that point, his CD4 count was 430 cells per mcL, or 23.5% of total T cells. The CD4:CD8 ratio was 0.86; normal range is 1.5-2.5.

The researchers used quantitative real-time polymerase chain reaction (rt-PCR) to look for packaging site and envelope (env) DNA fragments, and droplet digital PCR to quantify HIV-1 DNA.

The patient’s HIV-1 plasma load measured at 30 months post ATI on an ultrasensitive assay was below the lower limit of detection (less than 1 copy per mL). Semen viremia measured at 21 months was also below the lower limit of detection, as was CSF measured at 25 months.

Samples were taken from the patient’s rectum, cecum, sigmoid colon, and terminal ileum during a colonoscopy conducted 22 months post ATI; all tested negative for HIV DNA via droplet digital PCR.

The lymph node had large numbers of EBV-positive cells and was positive for HIV-1 env and long-terminal repeat by double-drop PCR, but no integrase DNA was detected. Additionally, no intact proviral DNA was found on assay.

Dr. Gupta and associates speculated that “EBV reactivation could have triggered EBV-specific CD4 and CD8 T-cell responses and proliferation, potentially including CD4 T cells containing HIV-1 DNA.” Supporting this hypothesis, EBV-specific CD8 T-cell responses in peripheral blood were “robust,” and the researchers also saw some CD4 response.

“Similar to the Berlin patient, highly sensitive tests showed very low levels of so-called fossilized HIV-1 DNA in some tissue samples from the London patient. Residual HIV-1 DNA and axillary lymph node tissue could represent a defective clone that expanded during hyperplasia within the lymph note sampled,” noted Dr. Gupta and coauthors.

Responses of CD4 and CD8 T cells to HIV have also remained below the limit of detection, though cytomegalovirus-specific responses persist in the London patient.

As with the Berlin patient, standard enzyme-linked immunosorbent assay (ELISA) testing has remained positive in the London patient. “Standard ELISA testing, therefore, cannot be used as a marker for cure, although more work needs to be done to assess the role of detuned low-avidity antibody assays in defining cure,” noted Dr. Gupta and associates.

The ongoing follow-up plan for the London patient is to obtain viral load testing twice yearly up to 5 years post ATI, and then obtain yearly tests for a total of 10 years. Ongoing testing will confirm the investigators’ belief that “these findings probably represent the second recorded HIV-1 cure after CCR5 delta-32/delta-32 allo-HSCT, with evidence of residual low-level HIV-1 DNA.”

Dr. Zerbato and Dr. Lewin advised cautious optimism and ongoing surveillance: “In view of the many cells sampled in this case, and the absence of any intact virus, is the London patient truly cured? The additional data provided in this follow-up case report is certainly exciting and encouraging but, in the end, only time will tell.”

Dr. Gupta reported being a consultant for ViiV Healthcare and Gilead Sciences; several coauthors also reported financial relationships with pharmaceutical companies. The work was funded by amfAR, the American Foundation for AIDS Research, and the Wellcome Trust. Dr. Lewin reported grants from the National Health and Medical Research Council of Australia, the National Institutes of Health, the American Foundation for AIDS Research, Gilead Sciences, Merck, ViiV Healthcare, Leidos, the Wellcome Trust, the Australian Centre for HIV and Hepatitis Virology Research, and the Melbourne HIV Cure Consortium. Dr. Zerbato reported grants from the Melbourne HIV Cure Consortium,

[email protected]

SOURCE: Gupta R et al. Lancet. 2020 Mar 10. doi: 10.1016/ S2352-3018(20)30069-2.

A patient with HIV remission induced by stem cell transplantation continues to be disease free at the 30-month mark.

The individual, referred to as the London patient, received allogeneic hematopoietic stem cell transplantation (allo-HSCT) for stage IVB Hodgkin lymphoma. The transplant donor was homozygous for the CCR5 delta-32 mutation, which confers immunity to HIV because there’s no point of entry for the virus into immune cells.

After extensive sampling of various tissues, including gut, lymph node, blood, semen, and cerebrospinal fluid (CSF), Ravindra Kumar Gupta, MD, PhD, and colleagues found no detectable virus that was competent to replicate. However, they reported that the testing did detect some “fossilized” remnants of HIV DNA persisting in certain tissues.

The results were shared in a video presentation of the research during the Conference on Retroviruses & Opportunistic Infections, which was presented online this year. CROI organizers chose to hold a virtual meeting because of concerns about the spread of COVID-19.

The London patient’s HIV status had been reported the previous year at CROI 2019, but only blood samples were used in that analysis.

In a commentary accompanying the simultaneously published study in the Lancet, Jennifer Zerbato, PhD, and Sharon Lewin, FRACP, PHD, FAAHMS, asked: “A key question now for the area of HIV cure is how soon can one know if someone has been cured of HIV?

“We will need more than a handful of patients cured of HIV to really understand the duration of follow-up needed and the likelihood of an unexpected late rebound in virus replication,” continued Dr. Zerbato, of the University of Melbourne, and Dr. Lewin, of the Royal Melbourne Hospital and Monash University, also in Melbourne.

In their ongoing analysis of data from the London patient, Dr. Gupta, a virologist at the University of Cambridge (England), and associates constructed a mathematical model that maps the probability for lifetime remission or cure of HIV against several factors, including the degree of chimerism achieved with the stem cell transplant.

In this model, when chimerism reaches 80% in total HIV target cells, the probability of remission for life is 98%; when donor chimerism reaches 90%, the probability of lifetime remission is greater than 99%. Peripheral T-cell chimerism in the London patient has held steady at 99%.

Dr. Gupta and associates obtained some testing opportunistically: A PET-CT scan revealed an axillary lymph node that was biopsied after it was found to have avid radiotracer uptake. Similarly, the CSF sample was obtained in the course of a work-up for some neurologic symptoms that the London patient was having.

In contrast to the first patient who achieved ongoing HIV remission from a pair of stem cell transplants received over 13 years ago – the Berlin patient – the London patient did not receive whole-body radiation, but rather underwent a reduced-intensity conditioning regimen. The London patient experienced a bout of gut graft-versus-host disease (GVHD) about 2 months after his transplant, but has been free of GVHD in the interval. He hasn’t taken cytotoxic agents or any GVHD prophylaxis since 6 months post transplant.

Though there’s no sign of HIV that’s competent to replicate, “the London patient has shown somewhat slow CD4 reconstitution,” said Dr. Gupta and coauthors in discussing the results.

The patient had a reactivation of Epstein-Barr virus (EBV) about 21 months after analytic treatment interruption (ATI) of antiretroviral therapy that was managed without any specific treatment, but he hasn’t experienced any opportunistic infections. However, his CD4 count didn’t rebound to pretransplant levels until 28 months after ATI. At that point, his CD4 count was 430 cells per mcL, or 23.5% of total T cells. The CD4:CD8 ratio was 0.86; normal range is 1.5-2.5.

The researchers used quantitative real-time polymerase chain reaction (rt-PCR) to look for packaging site and envelope (env) DNA fragments, and droplet digital PCR to quantify HIV-1 DNA.

The patient’s HIV-1 plasma load measured at 30 months post ATI on an ultrasensitive assay was below the lower limit of detection (less than 1 copy per mL). Semen viremia measured at 21 months was also below the lower limit of detection, as was CSF measured at 25 months.

Samples were taken from the patient’s rectum, cecum, sigmoid colon, and terminal ileum during a colonoscopy conducted 22 months post ATI; all tested negative for HIV DNA via droplet digital PCR.

The lymph node had large numbers of EBV-positive cells and was positive for HIV-1 env and long-terminal repeat by double-drop PCR, but no integrase DNA was detected. Additionally, no intact proviral DNA was found on assay.

Dr. Gupta and associates speculated that “EBV reactivation could have triggered EBV-specific CD4 and CD8 T-cell responses and proliferation, potentially including CD4 T cells containing HIV-1 DNA.” Supporting this hypothesis, EBV-specific CD8 T-cell responses in peripheral blood were “robust,” and the researchers also saw some CD4 response.

“Similar to the Berlin patient, highly sensitive tests showed very low levels of so-called fossilized HIV-1 DNA in some tissue samples from the London patient. Residual HIV-1 DNA and axillary lymph node tissue could represent a defective clone that expanded during hyperplasia within the lymph note sampled,” noted Dr. Gupta and coauthors.

Responses of CD4 and CD8 T cells to HIV have also remained below the limit of detection, though cytomegalovirus-specific responses persist in the London patient.

As with the Berlin patient, standard enzyme-linked immunosorbent assay (ELISA) testing has remained positive in the London patient. “Standard ELISA testing, therefore, cannot be used as a marker for cure, although more work needs to be done to assess the role of detuned low-avidity antibody assays in defining cure,” noted Dr. Gupta and associates.

The ongoing follow-up plan for the London patient is to obtain viral load testing twice yearly up to 5 years post ATI, and then obtain yearly tests for a total of 10 years. Ongoing testing will confirm the investigators’ belief that “these findings probably represent the second recorded HIV-1 cure after CCR5 delta-32/delta-32 allo-HSCT, with evidence of residual low-level HIV-1 DNA.”

Dr. Zerbato and Dr. Lewin advised cautious optimism and ongoing surveillance: “In view of the many cells sampled in this case, and the absence of any intact virus, is the London patient truly cured? The additional data provided in this follow-up case report is certainly exciting and encouraging but, in the end, only time will tell.”

Dr. Gupta reported being a consultant for ViiV Healthcare and Gilead Sciences; several coauthors also reported financial relationships with pharmaceutical companies. The work was funded by amfAR, the American Foundation for AIDS Research, and the Wellcome Trust. Dr. Lewin reported grants from the National Health and Medical Research Council of Australia, the National Institutes of Health, the American Foundation for AIDS Research, Gilead Sciences, Merck, ViiV Healthcare, Leidos, the Wellcome Trust, the Australian Centre for HIV and Hepatitis Virology Research, and the Melbourne HIV Cure Consortium. Dr. Zerbato reported grants from the Melbourne HIV Cure Consortium,

[email protected]

SOURCE: Gupta R et al. Lancet. 2020 Mar 10. doi: 10.1016/ S2352-3018(20)30069-2.

A patient with HIV remission induced by stem cell transplantation continues to be disease free at the 30-month mark.

The individual, referred to as the London patient, received allogeneic hematopoietic stem cell transplantation (allo-HSCT) for stage IVB Hodgkin lymphoma. The transplant donor was homozygous for the CCR5 delta-32 mutation, which confers immunity to HIV because there’s no point of entry for the virus into immune cells.

After extensive sampling of various tissues, including gut, lymph node, blood, semen, and cerebrospinal fluid (CSF), Ravindra Kumar Gupta, MD, PhD, and colleagues found no detectable virus that was competent to replicate. However, they reported that the testing did detect some “fossilized” remnants of HIV DNA persisting in certain tissues.

The results were shared in a video presentation of the research during the Conference on Retroviruses & Opportunistic Infections, which was presented online this year. CROI organizers chose to hold a virtual meeting because of concerns about the spread of COVID-19.

The London patient’s HIV status had been reported the previous year at CROI 2019, but only blood samples were used in that analysis.

In a commentary accompanying the simultaneously published study in the Lancet, Jennifer Zerbato, PhD, and Sharon Lewin, FRACP, PHD, FAAHMS, asked: “A key question now for the area of HIV cure is how soon can one know if someone has been cured of HIV?

“We will need more than a handful of patients cured of HIV to really understand the duration of follow-up needed and the likelihood of an unexpected late rebound in virus replication,” continued Dr. Zerbato, of the University of Melbourne, and Dr. Lewin, of the Royal Melbourne Hospital and Monash University, also in Melbourne.

In their ongoing analysis of data from the London patient, Dr. Gupta, a virologist at the University of Cambridge (England), and associates constructed a mathematical model that maps the probability for lifetime remission or cure of HIV against several factors, including the degree of chimerism achieved with the stem cell transplant.

In this model, when chimerism reaches 80% in total HIV target cells, the probability of remission for life is 98%; when donor chimerism reaches 90%, the probability of lifetime remission is greater than 99%. Peripheral T-cell chimerism in the London patient has held steady at 99%.

Dr. Gupta and associates obtained some testing opportunistically: A PET-CT scan revealed an axillary lymph node that was biopsied after it was found to have avid radiotracer uptake. Similarly, the CSF sample was obtained in the course of a work-up for some neurologic symptoms that the London patient was having.

In contrast to the first patient who achieved ongoing HIV remission from a pair of stem cell transplants received over 13 years ago – the Berlin patient – the London patient did not receive whole-body radiation, but rather underwent a reduced-intensity conditioning regimen. The London patient experienced a bout of gut graft-versus-host disease (GVHD) about 2 months after his transplant, but has been free of GVHD in the interval. He hasn’t taken cytotoxic agents or any GVHD prophylaxis since 6 months post transplant.

Though there’s no sign of HIV that’s competent to replicate, “the London patient has shown somewhat slow CD4 reconstitution,” said Dr. Gupta and coauthors in discussing the results.

The patient had a reactivation of Epstein-Barr virus (EBV) about 21 months after analytic treatment interruption (ATI) of antiretroviral therapy that was managed without any specific treatment, but he hasn’t experienced any opportunistic infections. However, his CD4 count didn’t rebound to pretransplant levels until 28 months after ATI. At that point, his CD4 count was 430 cells per mcL, or 23.5% of total T cells. The CD4:CD8 ratio was 0.86; normal range is 1.5-2.5.

The researchers used quantitative real-time polymerase chain reaction (rt-PCR) to look for packaging site and envelope (env) DNA fragments, and droplet digital PCR to quantify HIV-1 DNA.

The patient’s HIV-1 plasma load measured at 30 months post ATI on an ultrasensitive assay was below the lower limit of detection (less than 1 copy per mL). Semen viremia measured at 21 months was also below the lower limit of detection, as was CSF measured at 25 months.

Samples were taken from the patient’s rectum, cecum, sigmoid colon, and terminal ileum during a colonoscopy conducted 22 months post ATI; all tested negative for HIV DNA via droplet digital PCR.

The lymph node had large numbers of EBV-positive cells and was positive for HIV-1 env and long-terminal repeat by double-drop PCR, but no integrase DNA was detected. Additionally, no intact proviral DNA was found on assay.

Dr. Gupta and associates speculated that “EBV reactivation could have triggered EBV-specific CD4 and CD8 T-cell responses and proliferation, potentially including CD4 T cells containing HIV-1 DNA.” Supporting this hypothesis, EBV-specific CD8 T-cell responses in peripheral blood were “robust,” and the researchers also saw some CD4 response.

“Similar to the Berlin patient, highly sensitive tests showed very low levels of so-called fossilized HIV-1 DNA in some tissue samples from the London patient. Residual HIV-1 DNA and axillary lymph node tissue could represent a defective clone that expanded during hyperplasia within the lymph note sampled,” noted Dr. Gupta and coauthors.

Responses of CD4 and CD8 T cells to HIV have also remained below the limit of detection, though cytomegalovirus-specific responses persist in the London patient.

As with the Berlin patient, standard enzyme-linked immunosorbent assay (ELISA) testing has remained positive in the London patient. “Standard ELISA testing, therefore, cannot be used as a marker for cure, although more work needs to be done to assess the role of detuned low-avidity antibody assays in defining cure,” noted Dr. Gupta and associates.

The ongoing follow-up plan for the London patient is to obtain viral load testing twice yearly up to 5 years post ATI, and then obtain yearly tests for a total of 10 years. Ongoing testing will confirm the investigators’ belief that “these findings probably represent the second recorded HIV-1 cure after CCR5 delta-32/delta-32 allo-HSCT, with evidence of residual low-level HIV-1 DNA.”

Dr. Zerbato and Dr. Lewin advised cautious optimism and ongoing surveillance: “In view of the many cells sampled in this case, and the absence of any intact virus, is the London patient truly cured? The additional data provided in this follow-up case report is certainly exciting and encouraging but, in the end, only time will tell.”

Dr. Gupta reported being a consultant for ViiV Healthcare and Gilead Sciences; several coauthors also reported financial relationships with pharmaceutical companies. The work was funded by amfAR, the American Foundation for AIDS Research, and the Wellcome Trust. Dr. Lewin reported grants from the National Health and Medical Research Council of Australia, the National Institutes of Health, the American Foundation for AIDS Research, Gilead Sciences, Merck, ViiV Healthcare, Leidos, the Wellcome Trust, the Australian Centre for HIV and Hepatitis Virology Research, and the Melbourne HIV Cure Consortium. Dr. Zerbato reported grants from the Melbourne HIV Cure Consortium,

[email protected]

SOURCE: Gupta R et al. Lancet. 2020 Mar 10. doi: 10.1016/ S2352-3018(20)30069-2.

Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) provides “robust, sustained efficacy” in patients with Hodgkin lymphoma, according to investigators.

In the ECHELON-1 trial, investigators compared A+AVD to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for stage III or IV Hodgkin lymphoma. The 3-year progression-free survival (PFS) was superior in patients who received A+AVD, and this benefit was seen across most subgroups.

David J. Straus, MD, of Memorial Sloan Kettering Cancer Center in New York and his colleagues detailed these findings in Blood.

The phase 3 trial (NCT01712490) enrolled 1,334 patients with stage III or IV classical Hodgkin lymphoma. They were randomized to receive A+AVD (n = 664) or ABVD (n = 670). Baseline characteristics were similar between the treatment arms.

Positron emission tomography status after cycle 2 (PET2) was similar between the treatment arms as well. Most patients – 89% of the A+AVD arm and 86% of the ABVD arm – were PET2 negative. Treating physicians used PET2 status as a guide to potentially switch patients to an alternative regimen (radiotherapy or chemotherapy with or without transplant).

In a prior analysis, the study’s primary endpoint was modified PFS (time to progression, death, or noncomplete response after frontline therapy) per an independent review committee (N Engl J Med. 2018;378:331-44). The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm (hazard ratio, 0.77; P = .04).

PFS update

In the current analysis, the main exploratory endpoint was PFS per investigator. The 3-year PFS rate was significantly higher in the A+AVD arm than in the ABVD arm – 83.1% and 76.0%, respectively (HR, 0.704; P = .005).

The investigators observed a “consistent improvement in PFS” in the A+AVD arm, regardless of disease stage, International Prognostic score, Eastern Cooperative Oncology Group status, sex, or age. There was a significant improvement in PFS with A+AVD in PET2-negative patients and a trend toward improvement in PET2-positive patients. In the PET2-negative patients, the 3-year PFS was 85.8% in the A+AVD arm and 79.5% in the ABVD arm (HR, 0.69; P = .009). In PET2-positive patients, the 3-year PFS was 67.7% and 51.5%, respectively (HR, 0.59; P = .077).

“These data highlight that A+AVD provides a durable efficacy benefit, compared with ABVD, for frontline stage III/IV cHL [classical Hodgkin lymphoma], which is consistent across key subgroups regardless of patient status at PET2,” Dr. Straus and his colleagues wrote.

Safety update

In both treatment arms, peripheral neuropathy continued to improve or resolve with longer follow-up. Among patients who developed peripheral neuropathy, 78% in the A+AVD arm and 83% in the ABVD arm had improvement or resolution of the condition at 3 years.

Most patients had complete resolution of peripheral neuropathy; 62% in the A+AVD arm and 73% in the ABVD arm. The median time to complete resolution was 28 weeks (range, 0-167 weeks) after stopping A+AVD and 14 weeks (range, 0-188 weeks) after stopping ABVD.

The incidence of secondary malignancies was similar between the treatment arms. There were 14 secondary malignancies in the A+AVD arm (6 solid tumors, 8 hematologic malignancies) and 20 in the ABVD arm (9 solid tumors, 11 hematologic malignancies).

“A+AVD provided a sustained PFS benefit with a predictable and manageable safety profile,” Dr. Straus and colleagues wrote. “These data further support the advantages of A+AVD versus ABVD as frontline treatment of patients with advanced stage III or IV cHL [classical Hodgkin lymphoma].”

The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals (a subsidiary of Takeda) and Seattle Genetics. The investigators disclosed relationships with Millennium, Takeda, Seattle Genetics, and a range of other companies.

[email protected]

SOURCE: Straus DJ et al. Blood. 2020 Jan 16. pii: blood.2019003127. doi: 10.1182/blood.2019003127.

Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) provides “robust, sustained efficacy” in patients with Hodgkin lymphoma, according to investigators.

In the ECHELON-1 trial, investigators compared A+AVD to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for stage III or IV Hodgkin lymphoma. The 3-year progression-free survival (PFS) was superior in patients who received A+AVD, and this benefit was seen across most subgroups.

David J. Straus, MD, of Memorial Sloan Kettering Cancer Center in New York and his colleagues detailed these findings in Blood.

The phase 3 trial (NCT01712490) enrolled 1,334 patients with stage III or IV classical Hodgkin lymphoma. They were randomized to receive A+AVD (n = 664) or ABVD (n = 670). Baseline characteristics were similar between the treatment arms.

Positron emission tomography status after cycle 2 (PET2) was similar between the treatment arms as well. Most patients – 89% of the A+AVD arm and 86% of the ABVD arm – were PET2 negative. Treating physicians used PET2 status as a guide to potentially switch patients to an alternative regimen (radiotherapy or chemotherapy with or without transplant).

In a prior analysis, the study’s primary endpoint was modified PFS (time to progression, death, or noncomplete response after frontline therapy) per an independent review committee (N Engl J Med. 2018;378:331-44). The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm (hazard ratio, 0.77; P = .04).

PFS update

In the current analysis, the main exploratory endpoint was PFS per investigator. The 3-year PFS rate was significantly higher in the A+AVD arm than in the ABVD arm – 83.1% and 76.0%, respectively (HR, 0.704; P = .005).

The investigators observed a “consistent improvement in PFS” in the A+AVD arm, regardless of disease stage, International Prognostic score, Eastern Cooperative Oncology Group status, sex, or age. There was a significant improvement in PFS with A+AVD in PET2-negative patients and a trend toward improvement in PET2-positive patients. In the PET2-negative patients, the 3-year PFS was 85.8% in the A+AVD arm and 79.5% in the ABVD arm (HR, 0.69; P = .009). In PET2-positive patients, the 3-year PFS was 67.7% and 51.5%, respectively (HR, 0.59; P = .077).

“These data highlight that A+AVD provides a durable efficacy benefit, compared with ABVD, for frontline stage III/IV cHL [classical Hodgkin lymphoma], which is consistent across key subgroups regardless of patient status at PET2,” Dr. Straus and his colleagues wrote.

Safety update

In both treatment arms, peripheral neuropathy continued to improve or resolve with longer follow-up. Among patients who developed peripheral neuropathy, 78% in the A+AVD arm and 83% in the ABVD arm had improvement or resolution of the condition at 3 years.

Most patients had complete resolution of peripheral neuropathy; 62% in the A+AVD arm and 73% in the ABVD arm. The median time to complete resolution was 28 weeks (range, 0-167 weeks) after stopping A+AVD and 14 weeks (range, 0-188 weeks) after stopping ABVD.

The incidence of secondary malignancies was similar between the treatment arms. There were 14 secondary malignancies in the A+AVD arm (6 solid tumors, 8 hematologic malignancies) and 20 in the ABVD arm (9 solid tumors, 11 hematologic malignancies).

“A+AVD provided a sustained PFS benefit with a predictable and manageable safety profile,” Dr. Straus and colleagues wrote. “These data further support the advantages of A+AVD versus ABVD as frontline treatment of patients with advanced stage III or IV cHL [classical Hodgkin lymphoma].”

The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals (a subsidiary of Takeda) and Seattle Genetics. The investigators disclosed relationships with Millennium, Takeda, Seattle Genetics, and a range of other companies.

[email protected]

SOURCE: Straus DJ et al. Blood. 2020 Jan 16. pii: blood.2019003127. doi: 10.1182/blood.2019003127.

Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) provides “robust, sustained efficacy” in patients with Hodgkin lymphoma, according to investigators.

In the ECHELON-1 trial, investigators compared A+AVD to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for stage III or IV Hodgkin lymphoma. The 3-year progression-free survival (PFS) was superior in patients who received A+AVD, and this benefit was seen across most subgroups.

David J. Straus, MD, of Memorial Sloan Kettering Cancer Center in New York and his colleagues detailed these findings in Blood.

The phase 3 trial (NCT01712490) enrolled 1,334 patients with stage III or IV classical Hodgkin lymphoma. They were randomized to receive A+AVD (n = 664) or ABVD (n = 670). Baseline characteristics were similar between the treatment arms.

Positron emission tomography status after cycle 2 (PET2) was similar between the treatment arms as well. Most patients – 89% of the A+AVD arm and 86% of the ABVD arm – were PET2 negative. Treating physicians used PET2 status as a guide to potentially switch patients to an alternative regimen (radiotherapy or chemotherapy with or without transplant).

In a prior analysis, the study’s primary endpoint was modified PFS (time to progression, death, or noncomplete response after frontline therapy) per an independent review committee (N Engl J Med. 2018;378:331-44). The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm (hazard ratio, 0.77; P = .04).

PFS update

In the current analysis, the main exploratory endpoint was PFS per investigator. The 3-year PFS rate was significantly higher in the A+AVD arm than in the ABVD arm – 83.1% and 76.0%, respectively (HR, 0.704; P = .005).

The investigators observed a “consistent improvement in PFS” in the A+AVD arm, regardless of disease stage, International Prognostic score, Eastern Cooperative Oncology Group status, sex, or age. There was a significant improvement in PFS with A+AVD in PET2-negative patients and a trend toward improvement in PET2-positive patients. In the PET2-negative patients, the 3-year PFS was 85.8% in the A+AVD arm and 79.5% in the ABVD arm (HR, 0.69; P = .009). In PET2-positive patients, the 3-year PFS was 67.7% and 51.5%, respectively (HR, 0.59; P = .077).

“These data highlight that A+AVD provides a durable efficacy benefit, compared with ABVD, for frontline stage III/IV cHL [classical Hodgkin lymphoma], which is consistent across key subgroups regardless of patient status at PET2,” Dr. Straus and his colleagues wrote.

Safety update

In both treatment arms, peripheral neuropathy continued to improve or resolve with longer follow-up. Among patients who developed peripheral neuropathy, 78% in the A+AVD arm and 83% in the ABVD arm had improvement or resolution of the condition at 3 years.

Most patients had complete resolution of peripheral neuropathy; 62% in the A+AVD arm and 73% in the ABVD arm. The median time to complete resolution was 28 weeks (range, 0-167 weeks) after stopping A+AVD and 14 weeks (range, 0-188 weeks) after stopping ABVD.

The incidence of secondary malignancies was similar between the treatment arms. There were 14 secondary malignancies in the A+AVD arm (6 solid tumors, 8 hematologic malignancies) and 20 in the ABVD arm (9 solid tumors, 11 hematologic malignancies).

“A+AVD provided a sustained PFS benefit with a predictable and manageable safety profile,” Dr. Straus and colleagues wrote. “These data further support the advantages of A+AVD versus ABVD as frontline treatment of patients with advanced stage III or IV cHL [classical Hodgkin lymphoma].”

The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals (a subsidiary of Takeda) and Seattle Genetics. The investigators disclosed relationships with Millennium, Takeda, Seattle Genetics, and a range of other companies.

[email protected]

SOURCE: Straus DJ et al. Blood. 2020 Jan 16. pii: blood.2019003127. doi: 10.1182/blood.2019003127.

Adult survivors of pediatric cancers appear to be experiencing fewer major cardiac events in adulthood partly because of reduced radiotherapy exposure, especially among survivors of Hodgkin lymphoma, recent research published in BMJ has shown.

“Contemporary cancer treatment has focused on advancing cure rates while attempting to minimize long term adverse effects,” Daniel A. Mulrooney, MD, of the Division of Cancer Survivorship, Department of Oncology, at St. Jude Children’s Research Hospital, Arlington, Va., and colleagues wrote. “Patterns of exposure to cardiotoxic treatment have changed over time, with fewer children receiving chest directed radiation, with lower doses and smaller volumes for those who do, and an increased use of anthracyclines, albeit with reduced cumulative doses as the risk for late-onset heart failure became apparent.”

Although research has been published on improved survival rates of children who underwent cancer treatment in the 1990s, compared with those who received treatment in the 1980s and 1970s, Dr. Mulrooney and colleagues set out to determine whether cardiac outcomes were reduced as well. They conducted a retrospective study of 23,462 5-year survivors of pediatric cancer, which consisted of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft-tissue sarcomas, and bone sarcomas diagnosed between January 1970 and December 1999. Researchers compared the cardiac outcomes of the survivors, including heart failure, coronary artery disease, valvular heart disease, pericardial disease, and arrhythmias, with a comparison group of their siblings (n = 5,057) separated by decade. The adult survivors tended to be women (46% vs. 40%) with a median age of 6.1 years at diagnosis and 27.7 years at final follow-up.

Of the 6,193 participants treated for cancer in the 1970s, the 20-year cumulative incidence of heart failure was 0.69%, while the 9,363 participants treated in the 1980s had an incidence of 0.74%, and 7,906 participants in the 1990s had a cumulative incidence of 0.54% over 20 years. The 20-year cumulative incidence for coronary artery disease (CAD) was 0.38% for participants in the 1970s, 0.24% for participants in the 1980s, and 0.19% for participants in the 1990s (P less than .01). Researchers noted the 20-year cumulative incidence of valvular disease, pericardial disease, and arrhythmias did not decrease between the 1970s and the 1990s.

When comparing the rate of major cardiac events of participants in the 1980s and 1990s with those of the 1970s, CAD diagnoses significantly decreased in the 1980s (hazard ratio, 0.65; 95% confidence interval, 0.45-0.92) and 1990s (HR, 0.53; 95% CI, 0.36-0.77), while there was no significant decrease in heart failure or valvular heart disease risk over time. After adjusting for cardiac radiation, overall risk for CAD was attenuated (HR, 0.90; 0.78-1.05), and Hodgkin lymphoma survivors saw the greatest change between unadjusted (HR, 0.77; 95% CI, 0.66-0.89) and adjusted risk (HR, 0.87; 95% CI, 0.69-1.10) when accounting for cardiac radiation.

“While additional longitudinal follow-up is needed to establish whether similar reductions in the cumulative incidence of heart failure can be confirmed in multivariable analysis, these results suggest that efforts to modify cancer therapies in children and promote health surveillance for survivors are beginning to show benefits not only in overall survival but also in late adverse cardiac effects,” the researchers concluded.

In a related editorial, Mike Hawkins, DPhil, of the Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research at the University of Birmingham (England), and colleagues said that, while measuring cardiotoxicity is important for this patient population, traditional risk factors with independent associations to cardiac outcomes should also be studied. Guidelines on follow-up for these patients are also needed to inform clinical practice, such as those produced by the International Late Effects of Childhood Cancer Guideline Harmonization Group, they added.

“Survivorship issues are extremely important to patients, their families, and their doctors,” they said. “In two research priority setting initiatives in the United Kingdom, detailed consultation with patients with cancer, survivors, families, friends, and healthcare professionals identified further research into the consequences of cancer as a top priority.”

This study was funded by grants from the National Cancer Institute, Cancer Center Support (CORE) to St. Jude Children’s Research Hospital and American Lebanese Syrian Associated Charities. The authors of the study and the editorial reported no relevant conflicts of interest.

SOURCE: Mulrooney A et al. BMJ. 2020. doi: 10.1136/bmj.l6794.

Adult survivors of pediatric cancers appear to be experiencing fewer major cardiac events in adulthood partly because of reduced radiotherapy exposure, especially among survivors of Hodgkin lymphoma, recent research published in BMJ has shown.

“Contemporary cancer treatment has focused on advancing cure rates while attempting to minimize long term adverse effects,” Daniel A. Mulrooney, MD, of the Division of Cancer Survivorship, Department of Oncology, at St. Jude Children’s Research Hospital, Arlington, Va., and colleagues wrote. “Patterns of exposure to cardiotoxic treatment have changed over time, with fewer children receiving chest directed radiation, with lower doses and smaller volumes for those who do, and an increased use of anthracyclines, albeit with reduced cumulative doses as the risk for late-onset heart failure became apparent.”

Although research has been published on improved survival rates of children who underwent cancer treatment in the 1990s, compared with those who received treatment in the 1980s and 1970s, Dr. Mulrooney and colleagues set out to determine whether cardiac outcomes were reduced as well. They conducted a retrospective study of 23,462 5-year survivors of pediatric cancer, which consisted of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft-tissue sarcomas, and bone sarcomas diagnosed between January 1970 and December 1999. Researchers compared the cardiac outcomes of the survivors, including heart failure, coronary artery disease, valvular heart disease, pericardial disease, and arrhythmias, with a comparison group of their siblings (n = 5,057) separated by decade. The adult survivors tended to be women (46% vs. 40%) with a median age of 6.1 years at diagnosis and 27.7 years at final follow-up.

Of the 6,193 participants treated for cancer in the 1970s, the 20-year cumulative incidence of heart failure was 0.69%, while the 9,363 participants treated in the 1980s had an incidence of 0.74%, and 7,906 participants in the 1990s had a cumulative incidence of 0.54% over 20 years. The 20-year cumulative incidence for coronary artery disease (CAD) was 0.38% for participants in the 1970s, 0.24% for participants in the 1980s, and 0.19% for participants in the 1990s (P less than .01). Researchers noted the 20-year cumulative incidence of valvular disease, pericardial disease, and arrhythmias did not decrease between the 1970s and the 1990s.

When comparing the rate of major cardiac events of participants in the 1980s and 1990s with those of the 1970s, CAD diagnoses significantly decreased in the 1980s (hazard ratio, 0.65; 95% confidence interval, 0.45-0.92) and 1990s (HR, 0.53; 95% CI, 0.36-0.77), while there was no significant decrease in heart failure or valvular heart disease risk over time. After adjusting for cardiac radiation, overall risk for CAD was attenuated (HR, 0.90; 0.78-1.05), and Hodgkin lymphoma survivors saw the greatest change between unadjusted (HR, 0.77; 95% CI, 0.66-0.89) and adjusted risk (HR, 0.87; 95% CI, 0.69-1.10) when accounting for cardiac radiation.

“While additional longitudinal follow-up is needed to establish whether similar reductions in the cumulative incidence of heart failure can be confirmed in multivariable analysis, these results suggest that efforts to modify cancer therapies in children and promote health surveillance for survivors are beginning to show benefits not only in overall survival but also in late adverse cardiac effects,” the researchers concluded.

In a related editorial, Mike Hawkins, DPhil, of the Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research at the University of Birmingham (England), and colleagues said that, while measuring cardiotoxicity is important for this patient population, traditional risk factors with independent associations to cardiac outcomes should also be studied. Guidelines on follow-up for these patients are also needed to inform clinical practice, such as those produced by the International Late Effects of Childhood Cancer Guideline Harmonization Group, they added.

“Survivorship issues are extremely important to patients, their families, and their doctors,” they said. “In two research priority setting initiatives in the United Kingdom, detailed consultation with patients with cancer, survivors, families, friends, and healthcare professionals identified further research into the consequences of cancer as a top priority.”

This study was funded by grants from the National Cancer Institute, Cancer Center Support (CORE) to St. Jude Children’s Research Hospital and American Lebanese Syrian Associated Charities. The authors of the study and the editorial reported no relevant conflicts of interest.

SOURCE: Mulrooney A et al. BMJ. 2020. doi: 10.1136/bmj.l6794.

Adult survivors of pediatric cancers appear to be experiencing fewer major cardiac events in adulthood partly because of reduced radiotherapy exposure, especially among survivors of Hodgkin lymphoma, recent research published in BMJ has shown.

“Contemporary cancer treatment has focused on advancing cure rates while attempting to minimize long term adverse effects,” Daniel A. Mulrooney, MD, of the Division of Cancer Survivorship, Department of Oncology, at St. Jude Children’s Research Hospital, Arlington, Va., and colleagues wrote. “Patterns of exposure to cardiotoxic treatment have changed over time, with fewer children receiving chest directed radiation, with lower doses and smaller volumes for those who do, and an increased use of anthracyclines, albeit with reduced cumulative doses as the risk for late-onset heart failure became apparent.”

Although research has been published on improved survival rates of children who underwent cancer treatment in the 1990s, compared with those who received treatment in the 1980s and 1970s, Dr. Mulrooney and colleagues set out to determine whether cardiac outcomes were reduced as well. They conducted a retrospective study of 23,462 5-year survivors of pediatric cancer, which consisted of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft-tissue sarcomas, and bone sarcomas diagnosed between January 1970 and December 1999. Researchers compared the cardiac outcomes of the survivors, including heart failure, coronary artery disease, valvular heart disease, pericardial disease, and arrhythmias, with a comparison group of their siblings (n = 5,057) separated by decade. The adult survivors tended to be women (46% vs. 40%) with a median age of 6.1 years at diagnosis and 27.7 years at final follow-up.

Of the 6,193 participants treated for cancer in the 1970s, the 20-year cumulative incidence of heart failure was 0.69%, while the 9,363 participants treated in the 1980s had an incidence of 0.74%, and 7,906 participants in the 1990s had a cumulative incidence of 0.54% over 20 years. The 20-year cumulative incidence for coronary artery disease (CAD) was 0.38% for participants in the 1970s, 0.24% for participants in the 1980s, and 0.19% for participants in the 1990s (P less than .01). Researchers noted the 20-year cumulative incidence of valvular disease, pericardial disease, and arrhythmias did not decrease between the 1970s and the 1990s.

When comparing the rate of major cardiac events of participants in the 1980s and 1990s with those of the 1970s, CAD diagnoses significantly decreased in the 1980s (hazard ratio, 0.65; 95% confidence interval, 0.45-0.92) and 1990s (HR, 0.53; 95% CI, 0.36-0.77), while there was no significant decrease in heart failure or valvular heart disease risk over time. After adjusting for cardiac radiation, overall risk for CAD was attenuated (HR, 0.90; 0.78-1.05), and Hodgkin lymphoma survivors saw the greatest change between unadjusted (HR, 0.77; 95% CI, 0.66-0.89) and adjusted risk (HR, 0.87; 95% CI, 0.69-1.10) when accounting for cardiac radiation.

“While additional longitudinal follow-up is needed to establish whether similar reductions in the cumulative incidence of heart failure can be confirmed in multivariable analysis, these results suggest that efforts to modify cancer therapies in children and promote health surveillance for survivors are beginning to show benefits not only in overall survival but also in late adverse cardiac effects,” the researchers concluded.

In a related editorial, Mike Hawkins, DPhil, of the Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research at the University of Birmingham (England), and colleagues said that, while measuring cardiotoxicity is important for this patient population, traditional risk factors with independent associations to cardiac outcomes should also be studied. Guidelines on follow-up for these patients are also needed to inform clinical practice, such as those produced by the International Late Effects of Childhood Cancer Guideline Harmonization Group, they added.

“Survivorship issues are extremely important to patients, their families, and their doctors,” they said. “In two research priority setting initiatives in the United Kingdom, detailed consultation with patients with cancer, survivors, families, friends, and healthcare professionals identified further research into the consequences of cancer as a top priority.”

This study was funded by grants from the National Cancer Institute, Cancer Center Support (CORE) to St. Jude Children’s Research Hospital and American Lebanese Syrian Associated Charities. The authors of the study and the editorial reported no relevant conflicts of interest.

SOURCE: Mulrooney A et al. BMJ. 2020. doi: 10.1136/bmj.l6794.

Vitamin D deficiency is associated with worse progression-free and overall survival among patients with Hodgkin lymphoma, according to new study findings.

Sven Borchmann, MD, of the University of Cologne (Germany) and German Hodgkin Study Group and coauthors conducted a case-control study of 351 patients enrolled in the German Hodgkin Study Group trials who had available baseline serum samples. Pretreatment vitamin D levels were assessed and categorized as deficient (less than 30 nmol/L), insufficient (30-49 nmol/L), or sufficient (50 nmol/L or greater). The findings were published in the Journal of Clinical Oncology.

The researchers found that before starting treatment, 50% of patients were vitamin D deficient.

Patients with baseline vitamin D deficiency had significantly lower progression-free survival – 10.2% lower at 5 years and 17.6% lower at 10 years – compared with patients with either sufficient or insufficient vitamin D levels (P less than .001). They also had 2% lower overall survival at 5 years and 11.1% lower overall survival at 10 years (P less than .001).

The researchers also conducted preclinical studies in effort to understand the effect of vitamin D on Hodgkin lymphoma cells and in Hodgkin lymphoma tumor models.

They explored the effect of vitamin D on cultured Hodgkin lymphoma cell lines and saw a dose-response effect of calcitriol in reducing cell proliferation rates. They then looked at the effect of calcitriol on cell lines that were also exposed to doxorubicin or etoposide, and found calcitriol improved the cytotoxicity of these chemotherapy agents, especially at lower doses.

Finally, they conducted an in-vivo mouse study using Hodgkin lymphoma xenografts, and looked at whether vitamin D supplementation increased the effect of doxorubicin or etoposide. This revealed that chemotherapy and vitamin D supplementation together were significantly better at controlling tumor growth, compared with monotherapy with either vitamin D or doxorubicin and compared with placebo.

“On the basis of our study results and the limited toxicity of vitamin D replacement therapy, we would advocate for vitamin D deficiency screening and replacement to be incorporated into future randomized clinical trials to properly clarify the role of vitamin D replacement in HL [Hodgkin lymphoma],” the researchers wrote. “The goal of these trials should be to determine whether vitamin D replacement in HL improves outcome.”

No study funding information was reported. Dr. Borchmann reported honoraria and research funding from Takeda. Other authors reported financial disclosures related to Takeda, Roche, Bristol-Myers Squibb, and other companies.

SOURCE: Borchmann S et al. J Clin Oncol. 2019 Oct 17. doi:10.1200/JCO.19.00985.

Vitamin D deficiency is associated with worse progression-free and overall survival among patients with Hodgkin lymphoma, according to new study findings.

Sven Borchmann, MD, of the University of Cologne (Germany) and German Hodgkin Study Group and coauthors conducted a case-control study of 351 patients enrolled in the German Hodgkin Study Group trials who had available baseline serum samples. Pretreatment vitamin D levels were assessed and categorized as deficient (less than 30 nmol/L), insufficient (30-49 nmol/L), or sufficient (50 nmol/L or greater). The findings were published in the Journal of Clinical Oncology.

The researchers found that before starting treatment, 50% of patients were vitamin D deficient.

Patients with baseline vitamin D deficiency had significantly lower progression-free survival – 10.2% lower at 5 years and 17.6% lower at 10 years – compared with patients with either sufficient or insufficient vitamin D levels (P less than .001). They also had 2% lower overall survival at 5 years and 11.1% lower overall survival at 10 years (P less than .001).

The researchers also conducted preclinical studies in effort to understand the effect of vitamin D on Hodgkin lymphoma cells and in Hodgkin lymphoma tumor models.

They explored the effect of vitamin D on cultured Hodgkin lymphoma cell lines and saw a dose-response effect of calcitriol in reducing cell proliferation rates. They then looked at the effect of calcitriol on cell lines that were also exposed to doxorubicin or etoposide, and found calcitriol improved the cytotoxicity of these chemotherapy agents, especially at lower doses.

Finally, they conducted an in-vivo mouse study using Hodgkin lymphoma xenografts, and looked at whether vitamin D supplementation increased the effect of doxorubicin or etoposide. This revealed that chemotherapy and vitamin D supplementation together were significantly better at controlling tumor growth, compared with monotherapy with either vitamin D or doxorubicin and compared with placebo.

“On the basis of our study results and the limited toxicity of vitamin D replacement therapy, we would advocate for vitamin D deficiency screening and replacement to be incorporated into future randomized clinical trials to properly clarify the role of vitamin D replacement in HL [Hodgkin lymphoma],” the researchers wrote. “The goal of these trials should be to determine whether vitamin D replacement in HL improves outcome.”

No study funding information was reported. Dr. Borchmann reported honoraria and research funding from Takeda. Other authors reported financial disclosures related to Takeda, Roche, Bristol-Myers Squibb, and other companies.

SOURCE: Borchmann S et al. J Clin Oncol. 2019 Oct 17. doi:10.1200/JCO.19.00985.

Vitamin D deficiency is associated with worse progression-free and overall survival among patients with Hodgkin lymphoma, according to new study findings.

Sven Borchmann, MD, of the University of Cologne (Germany) and German Hodgkin Study Group and coauthors conducted a case-control study of 351 patients enrolled in the German Hodgkin Study Group trials who had available baseline serum samples. Pretreatment vitamin D levels were assessed and categorized as deficient (less than 30 nmol/L), insufficient (30-49 nmol/L), or sufficient (50 nmol/L or greater). The findings were published in the Journal of Clinical Oncology.

The researchers found that before starting treatment, 50% of patients were vitamin D deficient.

Patients with baseline vitamin D deficiency had significantly lower progression-free survival – 10.2% lower at 5 years and 17.6% lower at 10 years – compared with patients with either sufficient or insufficient vitamin D levels (P less than .001). They also had 2% lower overall survival at 5 years and 11.1% lower overall survival at 10 years (P less than .001).

The researchers also conducted preclinical studies in effort to understand the effect of vitamin D on Hodgkin lymphoma cells and in Hodgkin lymphoma tumor models.

They explored the effect of vitamin D on cultured Hodgkin lymphoma cell lines and saw a dose-response effect of calcitriol in reducing cell proliferation rates. They then looked at the effect of calcitriol on cell lines that were also exposed to doxorubicin or etoposide, and found calcitriol improved the cytotoxicity of these chemotherapy agents, especially at lower doses.

Finally, they conducted an in-vivo mouse study using Hodgkin lymphoma xenografts, and looked at whether vitamin D supplementation increased the effect of doxorubicin or etoposide. This revealed that chemotherapy and vitamin D supplementation together were significantly better at controlling tumor growth, compared with monotherapy with either vitamin D or doxorubicin and compared with placebo.

“On the basis of our study results and the limited toxicity of vitamin D replacement therapy, we would advocate for vitamin D deficiency screening and replacement to be incorporated into future randomized clinical trials to properly clarify the role of vitamin D replacement in HL [Hodgkin lymphoma],” the researchers wrote. “The goal of these trials should be to determine whether vitamin D replacement in HL improves outcome.”

No study funding information was reported. Dr. Borchmann reported honoraria and research funding from Takeda. Other authors reported financial disclosures related to Takeda, Roche, Bristol-Myers Squibb, and other companies.

SOURCE: Borchmann S et al. J Clin Oncol. 2019 Oct 17. doi:10.1200/JCO.19.00985.

Radiotherapy appears to be an essential component of the optimal treatment regimen for adults with early-stage favorable Hodgkin lymphoma, investigators in a randomized phase 3 trial asserted.

Among more than 600 patients with early-stage Hodgkin lymphoma who were positron-emission tomography (PET)–negative after two cycles of standard chemotherapy, 5-year progression-free survival was significantly better for patients who had also received involved-field radiotherapy, compared with those who had received chemotherapy alone.

The HD16 trial was designed to show whether using PET findings to opt for consolidation radiotherapy could be noninferior to the use of combined modality therapy (CMT) with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and radiation for all patients with early-stage favorable-risk disease.

“However, we failed to meet the primary objective of the trial as PET-guided omission of radiotherapy results in poorer tumor control compared with CMT. We therefore recommend proceeding with consolidation radiotherapy as a standard of care for patients achieving a metabolic response after two cycles of ABVD,” Michael Fuchs, MD, from the University Hospital of Cologne, Germany, and colleagues in the German Hodgkin Study Group wrote in the Journal of Clinical Oncology.

The investigators also found that patients who remained PET-positive after two cycles of ABVD were at high risk for treatment failure, particularly when a Deauville score of 4 was used as the minimum threshold for positivity.

Although CMT is associated with high cure rates for patients with Hodgkin lymphoma, clinicians are concerned about long-term toxicities and risk for second malignancies, which prompted investigators to see whether radiotherapy could be safely eliminated in some cases.

The HD16 investigators enrolled 1,150 patients aged 18-75 years with early-stage favorable Hodgkin lymphoma, and randomly assigned them to receive two cycles of ABVD with either 20 Gy of involved-field radiotherapy or PET-guided treatment in which involved-field radiation was eliminated for those patients who were PET-negative after chemotherapy, with PET negativity defined as a Deauville score less than 3.

After a median follow-up of 47 months, the 5-year progression-free survival rates among 628 PET-negative patients were 93.4% for those assigned to CMT, versus 86.1% for patients assigned to chemotherapy alone, which translated into a hazard ratio HR of 1.78 (95% confidence interval, 1.02-3.12; P = .040). The upper limit of the confidence interval exceeds the predefined noninferiority margin of 3.01, which indicates that eliminating radiation was clinically inferior.

The difference in progression-free survival rates between the treatment arms was primarily caused by a significant increase in disease recurrence in what would have been the involved field for patients in the ABVD-alone group (in-field recurrence rate, 9% vs. 2% for patients who received CMT; P = .0003). In contrast, there were no significant differences between the groups in out-of-field recurrences (5% vs. 4%, respectively).

Five-year overall survival rates were virtually identical between the treatment arms among PET-negative patients.

When the investigators compared all PET-negative with PET-positive patients (Deauville score 4), they saw that 5-year estimated progression-free survival rates were 93.1% vs. 80.9%, respectively, an absolute difference of 12.1% that translated into a HR of 2.94 (P less than .001). There were no significant differences by PET status in 5-year overall survival, however.

“We assume that the small radiation fields and doses used in our HD16 trial will induce fewer late adverse events than those reported in the literature. However, we cannot exclude an increased risk for certain late effects, such as breast cancer in very young women, as the risk for this specific second malignancy increases with younger age,” the researchers wrote.

The study was supported by grants from Deutsche Krebshilfe and the Swiss State Secretariat for Education, Research, and Innovation. Dr. Fuchs reported honoraria from Amgen, Affimed, Celgene, and Takeda. Multiple coauthors reported industry funding.

SOURCE: Fuchs M et al. J Clin Oncol. 2019 Sep 10. doi: 10.1200/JCO.19.00964.

Radiotherapy appears to be an essential component of the optimal treatment regimen for adults with early-stage favorable Hodgkin lymphoma, investigators in a randomized phase 3 trial asserted.

Among more than 600 patients with early-stage Hodgkin lymphoma who were positron-emission tomography (PET)–negative after two cycles of standard chemotherapy, 5-year progression-free survival was significantly better for patients who had also received involved-field radiotherapy, compared with those who had received chemotherapy alone.

The HD16 trial was designed to show whether using PET findings to opt for consolidation radiotherapy could be noninferior to the use of combined modality therapy (CMT) with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and radiation for all patients with early-stage favorable-risk disease.

“However, we failed to meet the primary objective of the trial as PET-guided omission of radiotherapy results in poorer tumor control compared with CMT. We therefore recommend proceeding with consolidation radiotherapy as a standard of care for patients achieving a metabolic response after two cycles of ABVD,” Michael Fuchs, MD, from the University Hospital of Cologne, Germany, and colleagues in the German Hodgkin Study Group wrote in the Journal of Clinical Oncology.

The investigators also found that patients who remained PET-positive after two cycles of ABVD were at high risk for treatment failure, particularly when a Deauville score of 4 was used as the minimum threshold for positivity.

Although CMT is associated with high cure rates for patients with Hodgkin lymphoma, clinicians are concerned about long-term toxicities and risk for second malignancies, which prompted investigators to see whether radiotherapy could be safely eliminated in some cases.

The HD16 investigators enrolled 1,150 patients aged 18-75 years with early-stage favorable Hodgkin lymphoma, and randomly assigned them to receive two cycles of ABVD with either 20 Gy of involved-field radiotherapy or PET-guided treatment in which involved-field radiation was eliminated for those patients who were PET-negative after chemotherapy, with PET negativity defined as a Deauville score less than 3.

After a median follow-up of 47 months, the 5-year progression-free survival rates among 628 PET-negative patients were 93.4% for those assigned to CMT, versus 86.1% for patients assigned to chemotherapy alone, which translated into a hazard ratio HR of 1.78 (95% confidence interval, 1.02-3.12; P = .040). The upper limit of the confidence interval exceeds the predefined noninferiority margin of 3.01, which indicates that eliminating radiation was clinically inferior.

The difference in progression-free survival rates between the treatment arms was primarily caused by a significant increase in disease recurrence in what would have been the involved field for patients in the ABVD-alone group (in-field recurrence rate, 9% vs. 2% for patients who received CMT; P = .0003). In contrast, there were no significant differences between the groups in out-of-field recurrences (5% vs. 4%, respectively).

Five-year overall survival rates were virtually identical between the treatment arms among PET-negative patients.

When the investigators compared all PET-negative with PET-positive patients (Deauville score 4), they saw that 5-year estimated progression-free survival rates were 93.1% vs. 80.9%, respectively, an absolute difference of 12.1% that translated into a HR of 2.94 (P less than .001). There were no significant differences by PET status in 5-year overall survival, however.

“We assume that the small radiation fields and doses used in our HD16 trial will induce fewer late adverse events than those reported in the literature. However, we cannot exclude an increased risk for certain late effects, such as breast cancer in very young women, as the risk for this specific second malignancy increases with younger age,” the researchers wrote.

The study was supported by grants from Deutsche Krebshilfe and the Swiss State Secretariat for Education, Research, and Innovation. Dr. Fuchs reported honoraria from Amgen, Affimed, Celgene, and Takeda. Multiple coauthors reported industry funding.

SOURCE: Fuchs M et al. J Clin Oncol. 2019 Sep 10. doi: 10.1200/JCO.19.00964.

Radiotherapy appears to be an essential component of the optimal treatment regimen for adults with early-stage favorable Hodgkin lymphoma, investigators in a randomized phase 3 trial asserted.

Among more than 600 patients with early-stage Hodgkin lymphoma who were positron-emission tomography (PET)–negative after two cycles of standard chemotherapy, 5-year progression-free survival was significantly better for patients who had also received involved-field radiotherapy, compared with those who had received chemotherapy alone.

The HD16 trial was designed to show whether using PET findings to opt for consolidation radiotherapy could be noninferior to the use of combined modality therapy (CMT) with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and radiation for all patients with early-stage favorable-risk disease.

“However, we failed to meet the primary objective of the trial as PET-guided omission of radiotherapy results in poorer tumor control compared with CMT. We therefore recommend proceeding with consolidation radiotherapy as a standard of care for patients achieving a metabolic response after two cycles of ABVD,” Michael Fuchs, MD, from the University Hospital of Cologne, Germany, and colleagues in the German Hodgkin Study Group wrote in the Journal of Clinical Oncology.

The investigators also found that patients who remained PET-positive after two cycles of ABVD were at high risk for treatment failure, particularly when a Deauville score of 4 was used as the minimum threshold for positivity.

Although CMT is associated with high cure rates for patients with Hodgkin lymphoma, clinicians are concerned about long-term toxicities and risk for second malignancies, which prompted investigators to see whether radiotherapy could be safely eliminated in some cases.

The HD16 investigators enrolled 1,150 patients aged 18-75 years with early-stage favorable Hodgkin lymphoma, and randomly assigned them to receive two cycles of ABVD with either 20 Gy of involved-field radiotherapy or PET-guided treatment in which involved-field radiation was eliminated for those patients who were PET-negative after chemotherapy, with PET negativity defined as a Deauville score less than 3.

After a median follow-up of 47 months, the 5-year progression-free survival rates among 628 PET-negative patients were 93.4% for those assigned to CMT, versus 86.1% for patients assigned to chemotherapy alone, which translated into a hazard ratio HR of 1.78 (95% confidence interval, 1.02-3.12; P = .040). The upper limit of the confidence interval exceeds the predefined noninferiority margin of 3.01, which indicates that eliminating radiation was clinically inferior.

The difference in progression-free survival rates between the treatment arms was primarily caused by a significant increase in disease recurrence in what would have been the involved field for patients in the ABVD-alone group (in-field recurrence rate, 9% vs. 2% for patients who received CMT; P = .0003). In contrast, there were no significant differences between the groups in out-of-field recurrences (5% vs. 4%, respectively).

Five-year overall survival rates were virtually identical between the treatment arms among PET-negative patients.

When the investigators compared all PET-negative with PET-positive patients (Deauville score 4), they saw that 5-year estimated progression-free survival rates were 93.1% vs. 80.9%, respectively, an absolute difference of 12.1% that translated into a HR of 2.94 (P less than .001). There were no significant differences by PET status in 5-year overall survival, however.

“We assume that the small radiation fields and doses used in our HD16 trial will induce fewer late adverse events than those reported in the literature. However, we cannot exclude an increased risk for certain late effects, such as breast cancer in very young women, as the risk for this specific second malignancy increases with younger age,” the researchers wrote.

The study was supported by grants from Deutsche Krebshilfe and the Swiss State Secretariat for Education, Research, and Innovation. Dr. Fuchs reported honoraria from Amgen, Affimed, Celgene, and Takeda. Multiple coauthors reported industry funding.

SOURCE: Fuchs M et al. J Clin Oncol. 2019 Sep 10. doi: 10.1200/JCO.19.00964.

AMSTERDAM – When predicting the risk of thromboembolism in lymphoma patients receiving chemotherapy, clinicians can rely on a routine diagnostic tool: complete blood count, investigators reported.

Will Pass/MDedge News

A recent study found that high neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios were prognostic for thromboembolism in this setting, reported lead author Vladimir Otasevic, MD, of the Clinical Centre of Serbia in Belgrade.

“Because of the presence of a broad spectrum of risk factors [in patients with lymphoma undergoing chemotherapy], some authors have published risk-assessment models for prediction of thromboembolism,” Dr. Otasevic said during a presentation at the annual congress of the European Hematology Association. While the underlying pathophysiology that precedes thromboembolism is complex, Dr. Otasevic suggested that risk prediction may not have to be, noting that NLR and PLR were recently proposed as risk biomarkers.

To test the utility of these potential biomarkers, Dr. Otasevic and his colleagues retrospectively analyzed data from 484 patients with non-Hodgkin and Hodgkin lymphoma who had undergone at least one cycle of chemotherapy at the Clinic for Hematology, Clinical Centre of Serbia. Patients were followed for venous and arterial thromboembolic events from the time of diagnosis to 3 months beyond their final cycle of chemotherapy. NLR and PLR ratios were calculated from complete blood count. Thromboembolism was diagnosed by radiography, clinical exam, and laboratory evaluation, with probable diagnoses reviewed by an internist and radiologist.

The median patient age was 53 years with a range from 18 to 89 years. Most patients were recently diagnosed with advanced disease (21.1% stage III and 42.5% stage IV). Half of the population had high-grade non-Hodgkin lymphoma (50.0%) and slightly more than a quarter had low-grade non-Hodgkin lymphoma (28.3%). Low-grade Hodgkin lymphoma was less common (17.4%) and followed distantly by other forms (4.3%).

Thirty-five patients (7.2%) developed thromboembolic events; of these, 30 had venous thromboembolism (6.2%), 6 had arterial thromboembolism (1.2%), and 1 had both. Patients who experienced thromboembolic events had significantly higher NLR and PLR than patients without thromboembolism, and both ratios were significantly associated with one another.

A positive NLR, defined as a ratio of 3.1 or more, was associated with a relative risk of 4.1 for thromboembolism (P less than .001), while a positive PLR, defined as a ratio of 10 or more, was associated with a relative risk of 2.9 (P = .008). Using a multivariate model, a positive NLR was associated with an even higher relative risk (RR = 4.5; P less than .001).

“NLR and PLR demonstrated significant powerfulness in prediction of future risk of [thromboembolism] in lymphoma patients,” the investigators concluded. “Simplicity, effectiveness, modesty, and practicability qualify these new tools for routine [thromboembolism] prognostic assessment.”

Dr. Otasevic said that he and his colleagues have plans to build on these findings with further analysis involving progression-free and overall survival.

The investigators reported no disclosures.

SOURCE: Otasevic V et al. EHA Congress, Abstract S1645.

AMSTERDAM – When predicting the risk of thromboembolism in lymphoma patients receiving chemotherapy, clinicians can rely on a routine diagnostic tool: complete blood count, investigators reported.

Will Pass/MDedge News

A recent study found that high neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios were prognostic for thromboembolism in this setting, reported lead author Vladimir Otasevic, MD, of the Clinical Centre of Serbia in Belgrade.

“Because of the presence of a broad spectrum of risk factors [in patients with lymphoma undergoing chemotherapy], some authors have published risk-assessment models for prediction of thromboembolism,” Dr. Otasevic said during a presentation at the annual congress of the European Hematology Association. While the underlying pathophysiology that precedes thromboembolism is complex, Dr. Otasevic suggested that risk prediction may not have to be, noting that NLR and PLR were recently proposed as risk biomarkers.

To test the utility of these potential biomarkers, Dr. Otasevic and his colleagues retrospectively analyzed data from 484 patients with non-Hodgkin and Hodgkin lymphoma who had undergone at least one cycle of chemotherapy at the Clinic for Hematology, Clinical Centre of Serbia. Patients were followed for venous and arterial thromboembolic events from the time of diagnosis to 3 months beyond their final cycle of chemotherapy. NLR and PLR ratios were calculated from complete blood count. Thromboembolism was diagnosed by radiography, clinical exam, and laboratory evaluation, with probable diagnoses reviewed by an internist and radiologist.

The median patient age was 53 years with a range from 18 to 89 years. Most patients were recently diagnosed with advanced disease (21.1% stage III and 42.5% stage IV). Half of the population had high-grade non-Hodgkin lymphoma (50.0%) and slightly more than a quarter had low-grade non-Hodgkin lymphoma (28.3%). Low-grade Hodgkin lymphoma was less common (17.4%) and followed distantly by other forms (4.3%).

Thirty-five patients (7.2%) developed thromboembolic events; of these, 30 had venous thromboembolism (6.2%), 6 had arterial thromboembolism (1.2%), and 1 had both. Patients who experienced thromboembolic events had significantly higher NLR and PLR than patients without thromboembolism, and both ratios were significantly associated with one another.

A positive NLR, defined as a ratio of 3.1 or more, was associated with a relative risk of 4.1 for thromboembolism (P less than .001), while a positive PLR, defined as a ratio of 10 or more, was associated with a relative risk of 2.9 (P = .008). Using a multivariate model, a positive NLR was associated with an even higher relative risk (RR = 4.5; P less than .001).

“NLR and PLR demonstrated significant powerfulness in prediction of future risk of [thromboembolism] in lymphoma patients,” the investigators concluded. “Simplicity, effectiveness, modesty, and practicability qualify these new tools for routine [thromboembolism] prognostic assessment.”

Dr. Otasevic said that he and his colleagues have plans to build on these findings with further analysis involving progression-free and overall survival.

The investigators reported no disclosures.

SOURCE: Otasevic V et al. EHA Congress, Abstract S1645.

AMSTERDAM – When predicting the risk of thromboembolism in lymphoma patients receiving chemotherapy, clinicians can rely on a routine diagnostic tool: complete blood count, investigators reported.

Will Pass/MDedge News

A recent study found that high neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios were prognostic for thromboembolism in this setting, reported lead author Vladimir Otasevic, MD, of the Clinical Centre of Serbia in Belgrade.

“Because of the presence of a broad spectrum of risk factors [in patients with lymphoma undergoing chemotherapy], some authors have published risk-assessment models for prediction of thromboembolism,” Dr. Otasevic said during a presentation at the annual congress of the European Hematology Association. While the underlying pathophysiology that precedes thromboembolism is complex, Dr. Otasevic suggested that risk prediction may not have to be, noting that NLR and PLR were recently proposed as risk biomarkers.

To test the utility of these potential biomarkers, Dr. Otasevic and his colleagues retrospectively analyzed data from 484 patients with non-Hodgkin and Hodgkin lymphoma who had undergone at least one cycle of chemotherapy at the Clinic for Hematology, Clinical Centre of Serbia. Patients were followed for venous and arterial thromboembolic events from the time of diagnosis to 3 months beyond their final cycle of chemotherapy. NLR and PLR ratios were calculated from complete blood count. Thromboembolism was diagnosed by radiography, clinical exam, and laboratory evaluation, with probable diagnoses reviewed by an internist and radiologist.

The median patient age was 53 years with a range from 18 to 89 years. Most patients were recently diagnosed with advanced disease (21.1% stage III and 42.5% stage IV). Half of the population had high-grade non-Hodgkin lymphoma (50.0%) and slightly more than a quarter had low-grade non-Hodgkin lymphoma (28.3%). Low-grade Hodgkin lymphoma was less common (17.4%) and followed distantly by other forms (4.3%).

Thirty-five patients (7.2%) developed thromboembolic events; of these, 30 had venous thromboembolism (6.2%), 6 had arterial thromboembolism (1.2%), and 1 had both. Patients who experienced thromboembolic events had significantly higher NLR and PLR than patients without thromboembolism, and both ratios were significantly associated with one another.

A positive NLR, defined as a ratio of 3.1 or more, was associated with a relative risk of 4.1 for thromboembolism (P less than .001), while a positive PLR, defined as a ratio of 10 or more, was associated with a relative risk of 2.9 (P = .008). Using a multivariate model, a positive NLR was associated with an even higher relative risk (RR = 4.5; P less than .001).

“NLR and PLR demonstrated significant powerfulness in prediction of future risk of [thromboembolism] in lymphoma patients,” the investigators concluded. “Simplicity, effectiveness, modesty, and practicability qualify these new tools for routine [thromboembolism] prognostic assessment.”

Dr. Otasevic said that he and his colleagues have plans to build on these findings with further analysis involving progression-free and overall survival.

The investigators reported no disclosures.

SOURCE: Otasevic V et al. EHA Congress, Abstract S1645.

A retrospective study suggests a four-drug regimen can be effective salvage therapy for patients with relapsed or refractory classical Hodgkin lymphoma.

The regimen – brentuximab vedotin plus ifosfamide, gemcitabine, and vinorelbine (BV-IGEV) – produced responses in 27 of 28 patients studied, allowing them to undergo autologous hematopoietic stem cell transplant (HSCT).

After HSCT, the estimated 2-year progression-free survival (PFS) was 87.1% and the overall survival (OS) was 73.5%.

Though this study was limited by its small population and retrospective nature, the results “warrant further investigation,” according to Khadega A. Abuelgasim, MD, of King Abdullah International Medical Research Center in Riyadh, Saudi Arabia, and colleagues.

The researchers reported the results in a letter to Bone Marrow Transplantation.

The study included 28 patients with classical Hodgkin lymphoma, 15 of them male. The patients’ median age at HSCT was 25 years (range, 15-49 years). Twenty patients (71%) had constitutional symptoms at diagnosis, and eight (29%) had bulky disease.

Twenty-three patients (82%) received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline therapy, and four (14%) received ABVD followed by escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. One patient received a different frontline regimen.

The median time to relapse was 7.9 months (range, 1.9-133 months), and 12 patients (43%) were refractory to frontline treatment.

Half of patients (n = 14) received BV-IGEV as first salvage. The regimen was given as follows: ifosfamide at 2,000 mg/m² on days 1-4, gemcitabine at 800 mg/m² on days 1 and 4, vinorelbine at 20 mg/m² on day 1, prednisolone at 100 mg on days 1-4, and BV at a dose of 1.8 mg/kg on day 1 of each 3-week IGEV course.

All patients received at least two cycles of BV-IGEV and were assessed for response after one or two cycles. The median follow-up was 17 months (range, 0-65 months).

Twenty patients (71%) had a complete metabolic response to BV-IGEV, seven (25%) had a partial metabolic response, and one patient (4%) had stable disease. The patient with stable disease went on to receive another salvage regimen and achieved a partial response to that regimen.

The most common adverse events during BV-IGEV treatment were grade 3-4 neutropenia (n = 27; 96%) and thrombocytopenia (n = 25; 89%). Febrile neutropenia was also common (n = 16; 57%), as were mucositis (n = 6; 21%) and diarrhea (n = 6; 21%). Six patients had a reduction in BV dose because of an adverse event.

All patients underwent autologous HSCT. They received carmustine, etoposide, cytarabine, and melphalan as conditioning beforehand, and 18 patients (64%) received consolidative BV after transplant.

PFS and OS were calculated from the date of stem cell infusion. The estimated 2-year PFS was 87.1%, and the estimated 2-year OS was 73.5%.

Patients who received BV-IGEV as first salvage fared better than those who received the regimen as second salvage. The PFS rates were 100% and 75%, respectively (P = .0078), and OS rates were 100% and 50%, respectively (P = .08).

Six patients relapsed after HSCT, and three died. Two patients died of progressive disease and one died of pulmonary infection.

These results suggest BV-IGEV can produce high response rates without compromising stem cell mobilization, but the combination should be investigated further, according to the researchers.

The researchers reported having no conflicts of interest.

[email protected]

SOURCE: Abuelgasim KA et al. Bone Marrow Transplant. 2019 Jan 30. doi: 10.1038/s41409-019-0454-z.

A retrospective study suggests a four-drug regimen can be effective salvage therapy for patients with relapsed or refractory classical Hodgkin lymphoma.

The regimen – brentuximab vedotin plus ifosfamide, gemcitabine, and vinorelbine (BV-IGEV) – produced responses in 27 of 28 patients studied, allowing them to undergo autologous hematopoietic stem cell transplant (HSCT).

After HSCT, the estimated 2-year progression-free survival (PFS) was 87.1% and the overall survival (OS) was 73.5%.

Though this study was limited by its small population and retrospective nature, the results “warrant further investigation,” according to Khadega A. Abuelgasim, MD, of King Abdullah International Medical Research Center in Riyadh, Saudi Arabia, and colleagues.

The researchers reported the results in a letter to Bone Marrow Transplantation.

The study included 28 patients with classical Hodgkin lymphoma, 15 of them male. The patients’ median age at HSCT was 25 years (range, 15-49 years). Twenty patients (71%) had constitutional symptoms at diagnosis, and eight (29%) had bulky disease.

Twenty-three patients (82%) received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline therapy, and four (14%) received ABVD followed by escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. One patient received a different frontline regimen.

The median time to relapse was 7.9 months (range, 1.9-133 months), and 12 patients (43%) were refractory to frontline treatment.

Half of patients (n = 14) received BV-IGEV as first salvage. The regimen was given as follows: ifosfamide at 2,000 mg/m² on days 1-4, gemcitabine at 800 mg/m² on days 1 and 4, vinorelbine at 20 mg/m² on day 1, prednisolone at 100 mg on days 1-4, and BV at a dose of 1.8 mg/kg on day 1 of each 3-week IGEV course.

All patients received at least two cycles of BV-IGEV and were assessed for response after one or two cycles. The median follow-up was 17 months (range, 0-65 months).

Twenty patients (71%) had a complete metabolic response to BV-IGEV, seven (25%) had a partial metabolic response, and one patient (4%) had stable disease. The patient with stable disease went on to receive another salvage regimen and achieved a partial response to that regimen.

The most common adverse events during BV-IGEV treatment were grade 3-4 neutropenia (n = 27; 96%) and thrombocytopenia (n = 25; 89%). Febrile neutropenia was also common (n = 16; 57%), as were mucositis (n = 6; 21%) and diarrhea (n = 6; 21%). Six patients had a reduction in BV dose because of an adverse event.

All patients underwent autologous HSCT. They received carmustine, etoposide, cytarabine, and melphalan as conditioning beforehand, and 18 patients (64%) received consolidative BV after transplant.

PFS and OS were calculated from the date of stem cell infusion. The estimated 2-year PFS was 87.1%, and the estimated 2-year OS was 73.5%.

Patients who received BV-IGEV as first salvage fared better than those who received the regimen as second salvage. The PFS rates were 100% and 75%, respectively (P = .0078), and OS rates were 100% and 50%, respectively (P = .08).

Six patients relapsed after HSCT, and three died. Two patients died of progressive disease and one died of pulmonary infection.

These results suggest BV-IGEV can produce high response rates without compromising stem cell mobilization, but the combination should be investigated further, according to the researchers.

The researchers reported having no conflicts of interest.

[email protected]

SOURCE: Abuelgasim KA et al. Bone Marrow Transplant. 2019 Jan 30. doi: 10.1038/s41409-019-0454-z.

A retrospective study suggests a four-drug regimen can be effective salvage therapy for patients with relapsed or refractory classical Hodgkin lymphoma.

The regimen – brentuximab vedotin plus ifosfamide, gemcitabine, and vinorelbine (BV-IGEV) – produced responses in 27 of 28 patients studied, allowing them to undergo autologous hematopoietic stem cell transplant (HSCT).

After HSCT, the estimated 2-year progression-free survival (PFS) was 87.1% and the overall survival (OS) was 73.5%.

Though this study was limited by its small population and retrospective nature, the results “warrant further investigation,” according to Khadega A. Abuelgasim, MD, of King Abdullah International Medical Research Center in Riyadh, Saudi Arabia, and colleagues.

The researchers reported the results in a letter to Bone Marrow Transplantation.

The study included 28 patients with classical Hodgkin lymphoma, 15 of them male. The patients’ median age at HSCT was 25 years (range, 15-49 years). Twenty patients (71%) had constitutional symptoms at diagnosis, and eight (29%) had bulky disease.

Twenty-three patients (82%) received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline therapy, and four (14%) received ABVD followed by escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. One patient received a different frontline regimen.

The median time to relapse was 7.9 months (range, 1.9-133 months), and 12 patients (43%) were refractory to frontline treatment.

Half of patients (n = 14) received BV-IGEV as first salvage. The regimen was given as follows: ifosfamide at 2,000 mg/m² on days 1-4, gemcitabine at 800 mg/m² on days 1 and 4, vinorelbine at 20 mg/m² on day 1, prednisolone at 100 mg on days 1-4, and BV at a dose of 1.8 mg/kg on day 1 of each 3-week IGEV course.

All patients received at least two cycles of BV-IGEV and were assessed for response after one or two cycles. The median follow-up was 17 months (range, 0-65 months).

Twenty patients (71%) had a complete metabolic response to BV-IGEV, seven (25%) had a partial metabolic response, and one patient (4%) had stable disease. The patient with stable disease went on to receive another salvage regimen and achieved a partial response to that regimen.

The most common adverse events during BV-IGEV treatment were grade 3-4 neutropenia (n = 27; 96%) and thrombocytopenia (n = 25; 89%). Febrile neutropenia was also common (n = 16; 57%), as were mucositis (n = 6; 21%) and diarrhea (n = 6; 21%). Six patients had a reduction in BV dose because of an adverse event.

All patients underwent autologous HSCT. They received carmustine, etoposide, cytarabine, and melphalan as conditioning beforehand, and 18 patients (64%) received consolidative BV after transplant.

PFS and OS were calculated from the date of stem cell infusion. The estimated 2-year PFS was 87.1%, and the estimated 2-year OS was 73.5%.

Patients who received BV-IGEV as first salvage fared better than those who received the regimen as second salvage. The PFS rates were 100% and 75%, respectively (P = .0078), and OS rates were 100% and 50%, respectively (P = .08).

Six patients relapsed after HSCT, and three died. Two patients died of progressive disease and one died of pulmonary infection.

These results suggest BV-IGEV can produce high response rates without compromising stem cell mobilization, but the combination should be investigated further, according to the researchers.

The researchers reported having no conflicts of interest.

[email protected]

SOURCE: Abuelgasim KA et al. Bone Marrow Transplant. 2019 Jan 30. doi: 10.1038/s41409-019-0454-z.

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

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

[email protected]