Lymphoma & Plasma Cell Disorders

Cpl Si Longworth RLC

People who have served in the Armed Forces do not have an increased risk of leukemia or lymphoma, according to research published in Cancer Epidemiology.

Researchers analyzed the long-term risks of developing leukemia, Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL) in veterans living in Scotland.

At a mean 30 years of follow-up, there were no significant differences in the risk of the aforementioned malignancies between veterans and non-veterans in Scotland.

This retrospective study included 56,205 veterans and 172,741 non-veterans.

The veterans’ earliest date of entering service was January 1960, and the latest date of leaving service was December 2012.

At a mean follow-up of 29.3 years, 294 (0.52%) veterans and 974 (0.56%) non-veterans were diagnosed with leukemia, HL, or NHL.

There were 125 (0.22%) cases of leukemia in veterans and 365 (0.21%) in non-veterans. There were 59 (0.10%) cases of HL in veterans and 182 (0.11%) in non-veterans. And there were 144 (0.26%) cases of NHL in veterans and 538 (0.31%) in non-veterans.

There was no significant difference in the risk of all 3 cancer types between the veterans and non-veterans. The unadjusted hazard ratio (HR) was 0.96 (P=0.541).

There were no significant differences in an adjusted analysis either. (The analysis was adjusted for regional deprivation, which takes into account information on income, employment, health, education, housing, crime, and access to services.)

The adjusted HR was 1.03 (P=0.773) for leukemias, 1.19 (P=0.272) for HL, and 0.86 (P=0.110) for NHL.

“This is an important study which provides reassurance that military service in the last 50 years does not increase people’s risk of leukemia overall,” said study author Beverly Bergman, PhD, of the University of Glasgow in the UK.

“The Armed Forces comply with all relevant health and safety legislation and regulations, and we can now see that their risk is no different from the general population.”

Cpl Si Longworth RLC

People who have served in the Armed Forces do not have an increased risk of leukemia or lymphoma, according to research published in Cancer Epidemiology.

Researchers analyzed the long-term risks of developing leukemia, Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL) in veterans living in Scotland.

At a mean 30 years of follow-up, there were no significant differences in the risk of the aforementioned malignancies between veterans and non-veterans in Scotland.

This retrospective study included 56,205 veterans and 172,741 non-veterans.

The veterans’ earliest date of entering service was January 1960, and the latest date of leaving service was December 2012.

At a mean follow-up of 29.3 years, 294 (0.52%) veterans and 974 (0.56%) non-veterans were diagnosed with leukemia, HL, or NHL.

There were 125 (0.22%) cases of leukemia in veterans and 365 (0.21%) in non-veterans. There were 59 (0.10%) cases of HL in veterans and 182 (0.11%) in non-veterans. And there were 144 (0.26%) cases of NHL in veterans and 538 (0.31%) in non-veterans.

There was no significant difference in the risk of all 3 cancer types between the veterans and non-veterans. The unadjusted hazard ratio (HR) was 0.96 (P=0.541).

There were no significant differences in an adjusted analysis either. (The analysis was adjusted for regional deprivation, which takes into account information on income, employment, health, education, housing, crime, and access to services.)

The adjusted HR was 1.03 (P=0.773) for leukemias, 1.19 (P=0.272) for HL, and 0.86 (P=0.110) for NHL.

“This is an important study which provides reassurance that military service in the last 50 years does not increase people’s risk of leukemia overall,” said study author Beverly Bergman, PhD, of the University of Glasgow in the UK.

“The Armed Forces comply with all relevant health and safety legislation and regulations, and we can now see that their risk is no different from the general population.”

Cpl Si Longworth RLC

People who have served in the Armed Forces do not have an increased risk of leukemia or lymphoma, according to research published in Cancer Epidemiology.

Researchers analyzed the long-term risks of developing leukemia, Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL) in veterans living in Scotland.

At a mean 30 years of follow-up, there were no significant differences in the risk of the aforementioned malignancies between veterans and non-veterans in Scotland.

This retrospective study included 56,205 veterans and 172,741 non-veterans.

The veterans’ earliest date of entering service was January 1960, and the latest date of leaving service was December 2012.

At a mean follow-up of 29.3 years, 294 (0.52%) veterans and 974 (0.56%) non-veterans were diagnosed with leukemia, HL, or NHL.

There were 125 (0.22%) cases of leukemia in veterans and 365 (0.21%) in non-veterans. There were 59 (0.10%) cases of HL in veterans and 182 (0.11%) in non-veterans. And there were 144 (0.26%) cases of NHL in veterans and 538 (0.31%) in non-veterans.

There was no significant difference in the risk of all 3 cancer types between the veterans and non-veterans. The unadjusted hazard ratio (HR) was 0.96 (P=0.541).

There were no significant differences in an adjusted analysis either. (The analysis was adjusted for regional deprivation, which takes into account information on income, employment, health, education, housing, crime, and access to services.)

The adjusted HR was 1.03 (P=0.773) for leukemias, 1.19 (P=0.272) for HL, and 0.86 (P=0.110) for NHL.

“This is an important study which provides reassurance that military service in the last 50 years does not increase people’s risk of leukemia overall,” said study author Beverly Bergman, PhD, of the University of Glasgow in the UK.

“The Armed Forces comply with all relevant health and safety legislation and regulations, and we can now see that their risk is no different from the general population.”

Photo courtesy of Merck

The US Food and Drug Administration (FDA) has granted accelerated approval for pembrolizumab (Keytruda) as a treatment for adult and pediatric patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response.

The drug, which is being developed by Merck, previously received FDA approval as a treatment for melanoma, lung cancer, and head and neck cancer.

Now, pembrolizumab has received accelerated approval to treat adult and pediatric patients with refractory cHL or those with cHL who have relapsed after 3 or more prior lines of therapy.

The accelerated approval was based on tumor response rate and durability of response. Continued approval of pembrolizumab for cHL patients may be contingent upon the verification and description of clinical benefit in confirmatory trials.

In adults with cHL, pembrolizumab is administered at a fixed dose of 200 mg every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

In pediatric patients with cHL, pembrolizumab is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Pembrolizumab trials

The FDA’s approval of pembrolizumab in adults with cHL is based on data from the phase 2 KEYNOTE-087 trial. (The following data were provided by Merck.)

The trial enrolled 210 patients who received pembrolizumab at a dose of 200 mg every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients who did not progress.

Fifty-eight percent of patients were refractory to their last prior therapy, including 35% with primary refractory disease and 14% whose disease was refractory to all prior regimens.

Sixty-one percent of patients had undergone prior autologous hematopoietic stem cell transplant, 83% had prior brentuximab use, and 36% had prior radiation therapy.

At a median follow-up of 9.4 months, the overall response rate was 69%, and the complete response rate was 22%. The median duration of response was 11.1 months (range, 0.0+ to 11.1 months).

Five percent of patients discontinued pembrolizumab due to adverse events (AEs), and 26% had dose interruptions due to AEs. Fifteen percent of patients had an AE requiring systemic corticosteroid therapy.

The most common AEs (occurring in ≥20% of patients) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

Serious AEs occurred in 16% of patients. The most frequent serious AEs (≥1%) were pneumonia, pneumonitis, pyrexia, dyspnea, graft-vs-host disease, and herpes zoster.

Two patients died from causes other than disease progression. One death was a result of graft-vs-host disease after subsequent allogeneic transplant, and the other was from septic shock.

There is limited experience with pembrolizumab in pediatric patients. The efficacy of the drug for pediatric patients was extrapolated from the results in the adult cHL population.

However, there is safety data on pembrolizumab in pediatric patients enrolled in the phase 1/2 KEYNOTE-051 trial. (These data were also provided by Merck.)

The trial included 40 pediatric patients with advanced melanoma or PD-L1–positive advanced, relapsed, or refractory solid tumors or lymphoma. Patients in this trial received pembrolizumab for a median of 43 days (range, 1-414 days).

The safety profile in these patients was similar to the profile in adults. Toxicities that occurred at a higher rate (≥15% difference) in pediatric patients than in adults under age 65 were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).

Photo courtesy of Merck

The US Food and Drug Administration (FDA) has granted accelerated approval for pembrolizumab (Keytruda) as a treatment for adult and pediatric patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response.

The drug, which is being developed by Merck, previously received FDA approval as a treatment for melanoma, lung cancer, and head and neck cancer.

Now, pembrolizumab has received accelerated approval to treat adult and pediatric patients with refractory cHL or those with cHL who have relapsed after 3 or more prior lines of therapy.

The accelerated approval was based on tumor response rate and durability of response. Continued approval of pembrolizumab for cHL patients may be contingent upon the verification and description of clinical benefit in confirmatory trials.

In adults with cHL, pembrolizumab is administered at a fixed dose of 200 mg every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

In pediatric patients with cHL, pembrolizumab is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Pembrolizumab trials

The FDA’s approval of pembrolizumab in adults with cHL is based on data from the phase 2 KEYNOTE-087 trial. (The following data were provided by Merck.)

The trial enrolled 210 patients who received pembrolizumab at a dose of 200 mg every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients who did not progress.

Fifty-eight percent of patients were refractory to their last prior therapy, including 35% with primary refractory disease and 14% whose disease was refractory to all prior regimens.

Sixty-one percent of patients had undergone prior autologous hematopoietic stem cell transplant, 83% had prior brentuximab use, and 36% had prior radiation therapy.

At a median follow-up of 9.4 months, the overall response rate was 69%, and the complete response rate was 22%. The median duration of response was 11.1 months (range, 0.0+ to 11.1 months).

Five percent of patients discontinued pembrolizumab due to adverse events (AEs), and 26% had dose interruptions due to AEs. Fifteen percent of patients had an AE requiring systemic corticosteroid therapy.

The most common AEs (occurring in ≥20% of patients) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

Serious AEs occurred in 16% of patients. The most frequent serious AEs (≥1%) were pneumonia, pneumonitis, pyrexia, dyspnea, graft-vs-host disease, and herpes zoster.

Two patients died from causes other than disease progression. One death was a result of graft-vs-host disease after subsequent allogeneic transplant, and the other was from septic shock.

There is limited experience with pembrolizumab in pediatric patients. The efficacy of the drug for pediatric patients was extrapolated from the results in the adult cHL population.

However, there is safety data on pembrolizumab in pediatric patients enrolled in the phase 1/2 KEYNOTE-051 trial. (These data were also provided by Merck.)

The trial included 40 pediatric patients with advanced melanoma or PD-L1–positive advanced, relapsed, or refractory solid tumors or lymphoma. Patients in this trial received pembrolizumab for a median of 43 days (range, 1-414 days).

The safety profile in these patients was similar to the profile in adults. Toxicities that occurred at a higher rate (≥15% difference) in pediatric patients than in adults under age 65 were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).

Photo courtesy of Merck

The US Food and Drug Administration (FDA) has granted accelerated approval for pembrolizumab (Keytruda) as a treatment for adult and pediatric patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response.

The drug, which is being developed by Merck, previously received FDA approval as a treatment for melanoma, lung cancer, and head and neck cancer.

Now, pembrolizumab has received accelerated approval to treat adult and pediatric patients with refractory cHL or those with cHL who have relapsed after 3 or more prior lines of therapy.

The accelerated approval was based on tumor response rate and durability of response. Continued approval of pembrolizumab for cHL patients may be contingent upon the verification and description of clinical benefit in confirmatory trials.

In adults with cHL, pembrolizumab is administered at a fixed dose of 200 mg every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

In pediatric patients with cHL, pembrolizumab is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Pembrolizumab trials

The FDA’s approval of pembrolizumab in adults with cHL is based on data from the phase 2 KEYNOTE-087 trial. (The following data were provided by Merck.)

The trial enrolled 210 patients who received pembrolizumab at a dose of 200 mg every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients who did not progress.

Fifty-eight percent of patients were refractory to their last prior therapy, including 35% with primary refractory disease and 14% whose disease was refractory to all prior regimens.

Sixty-one percent of patients had undergone prior autologous hematopoietic stem cell transplant, 83% had prior brentuximab use, and 36% had prior radiation therapy.

At a median follow-up of 9.4 months, the overall response rate was 69%, and the complete response rate was 22%. The median duration of response was 11.1 months (range, 0.0+ to 11.1 months).

Five percent of patients discontinued pembrolizumab due to adverse events (AEs), and 26% had dose interruptions due to AEs. Fifteen percent of patients had an AE requiring systemic corticosteroid therapy.

The most common AEs (occurring in ≥20% of patients) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

Serious AEs occurred in 16% of patients. The most frequent serious AEs (≥1%) were pneumonia, pneumonitis, pyrexia, dyspnea, graft-vs-host disease, and herpes zoster.

Two patients died from causes other than disease progression. One death was a result of graft-vs-host disease after subsequent allogeneic transplant, and the other was from septic shock.

There is limited experience with pembrolizumab in pediatric patients. The efficacy of the drug for pediatric patients was extrapolated from the results in the adult cHL population.

However, there is safety data on pembrolizumab in pediatric patients enrolled in the phase 1/2 KEYNOTE-051 trial. (These data were also provided by Merck.)

The trial included 40 pediatric patients with advanced melanoma or PD-L1–positive advanced, relapsed, or refractory solid tumors or lymphoma. Patients in this trial received pembrolizumab for a median of 43 days (range, 1-414 days).

The safety profile in these patients was similar to the profile in adults. Toxicities that occurred at a higher rate (≥15% difference) in pediatric patients than in adults under age 65 were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).

Photo by Rhoda Baer

A new study suggests Hodgkin lymphoma (HL) survivors have a high risk of developing a second malignancy, particularly if they have a family history of that malignancy.

The research showed that HL survivors in Sweden were roughly 2.4 times more likely than individuals in the country’s general population to develop a second cancer.

The risk for HL survivors remained high 30 years after treatment, and the risk was even greater in HL survivors who had a family history of specific cancers.

“The vast majority of patients with Hodgkin lymphoma are cured with a combination of chemotherapy and radiotherapy,” said study author Amit Sud, MBChB, of The Institute of Cancer Research, London in the UK.

“Our research has shown that these patients are at substantially increased risk of a second cancer later in life and particularly if they have a family history of cancer.”

Dr Sud and his colleagues described this research in the Journal of Clinical Oncology.

The team analyzed data from the Swedish Family-Cancer Project Database. They identified 9522 HL patients diagnosed between 1965 and 2013. During a median follow-up of 12.6 years, there were 1215 second cancers in 1121 HL patients (12%).

Compared to the general population, the HL patients had a significantly higher risk of all second malignancies, with a standardized incident ratio (SIR) of 2.39 and an absolute excess risk of 71.2 cases per 10,000 person-years.

Cancer types

HL patients had a significantly increased risk of several malignancies. The overall SIRs were as follows:

• NHL—7.99
• Leukemia—6.46
• Connective tissue cancer—5.73
• Thyroid cancer—5.13
• Squamous cell carcinoma—4.44
• Lung cancer—3.61
• Pharyngeal cancer—3.52
• Esophageal cancer—2.62
• Brain cancer—2.58
• Breast cancer—2.52
• Colon cancer—2.21
• Pancreatic cancer—2.09
• Melanoma—2.08
• Colorectal cancer—1.85
• Stomach cancer—1.78
• Bladder cancer—1.57
• Prostate cancer—1.21.

The researchers calculated SIRs over time and found the risk for many of the cancers remained high over 30 years following HL treatment.

Family history

The researchers identified 28,277 first-degree relatives of the HL survivors. Thirty percent of HL survivors (n=2785) had 1 or more first-degree relatives with a family history of cancer.

The SIR for cancers was 1.02 in the relatives. The SIR for second cancers was 2.83 for HL survivors who had first-degree relatives with cancer and 2.16 for HL survivors who did not have any first-degree relatives with cancer.

The researchers said the increased risk of second malignancy was correlated with the number of first-degree relatives with cancer.

The SIR was 2.67 for HL patients who had a single first-degree relative with cancer and 3.40 for HL patients who had 2 or more first-degree relatives with cancer.

The SIRs for different cancer types (for HL patients with at least 1 first-degree relative with cancer and no first-degree relatives with cancer, respectively) were as follows:

• NHL—14.43 vs 7.83
• Leukemia—14.31 vs 6.37
• Squamous cell carcinoma—10.85 vs 4.30
• Lung cancer—11.24 vs 3.39
• Breast cancer—4.36 vs 2.36
• Colorectal cancer—3.71 vs 1.76.

Sex and age

The researchers found significant differences in the SIRs for second cancers between HL patients diagnosed before the age of 35 and those diagnosed after age 35.

For men, the SIRs were:

• All cancers—4.26 for <35, 2.08 for ≥ 35
• Colorectal cancer—4.07 for < 35, 1.73 for ≥35
• Lung cancer—6.16 for < 35, 3.20 for ≥35
• Breast cancer—12.60 for < 35, 4.58 for ≥35
• Squamous cell carcinoma—5.89 for < 35, 3.96 for ≥35
• NHL—15.9 for < 35, 6.93 for ≥35
• Leukemia—12.15 for < 35, 5.57 for ≥35.

For women, the SIRs were:

• All cancers—4.61 for <35, 1.73 for ≥ 35
• Colorectal cancer—1.31 for < 35, 1.65 for ≥35
• Lung cancer—8.84 for < 35, 2.50 for ≥35
• Breast cancer—6.00 for < 35, 1.14 for ≥35
• Squamous cell carcinoma—6.37 for < 35, 4.87 for ≥35
• NHL—6.23 for < 35, 6.55 for ≥35
• Leukemia—10.36 for < 35, 4.51 for ≥35.

“Younger women who have been treated with radiotherapy to the chest for Hodgkin lymphoma are already screened for breast cancer, but our study suggests that we should be looking at ways of monitoring survivors for other forms of cancer too, and potentially offering preventative interventions,” Dr Sud said.

“After patients are cured, they no longer encounter oncologists, so it’s important that other healthcare providers are aware of the increased risk to Hodgkin lymphoma survivors to improve early diagnosis of second cancers.”

Photo by Rhoda Baer

A new study suggests Hodgkin lymphoma (HL) survivors have a high risk of developing a second malignancy, particularly if they have a family history of that malignancy.

The research showed that HL survivors in Sweden were roughly 2.4 times more likely than individuals in the country’s general population to develop a second cancer.

The risk for HL survivors remained high 30 years after treatment, and the risk was even greater in HL survivors who had a family history of specific cancers.

“The vast majority of patients with Hodgkin lymphoma are cured with a combination of chemotherapy and radiotherapy,” said study author Amit Sud, MBChB, of The Institute of Cancer Research, London in the UK.

“Our research has shown that these patients are at substantially increased risk of a second cancer later in life and particularly if they have a family history of cancer.”

Dr Sud and his colleagues described this research in the Journal of Clinical Oncology.

The team analyzed data from the Swedish Family-Cancer Project Database. They identified 9522 HL patients diagnosed between 1965 and 2013. During a median follow-up of 12.6 years, there were 1215 second cancers in 1121 HL patients (12%).

Compared to the general population, the HL patients had a significantly higher risk of all second malignancies, with a standardized incident ratio (SIR) of 2.39 and an absolute excess risk of 71.2 cases per 10,000 person-years.

Cancer types

HL patients had a significantly increased risk of several malignancies. The overall SIRs were as follows:

• NHL—7.99
• Leukemia—6.46
• Connective tissue cancer—5.73
• Thyroid cancer—5.13
• Squamous cell carcinoma—4.44
• Lung cancer—3.61
• Pharyngeal cancer—3.52
• Esophageal cancer—2.62
• Brain cancer—2.58
• Breast cancer—2.52
• Colon cancer—2.21
• Pancreatic cancer—2.09
• Melanoma—2.08
• Colorectal cancer—1.85
• Stomach cancer—1.78
• Bladder cancer—1.57
• Prostate cancer—1.21.

The researchers calculated SIRs over time and found the risk for many of the cancers remained high over 30 years following HL treatment.

Family history

The researchers identified 28,277 first-degree relatives of the HL survivors. Thirty percent of HL survivors (n=2785) had 1 or more first-degree relatives with a family history of cancer.

The SIR for cancers was 1.02 in the relatives. The SIR for second cancers was 2.83 for HL survivors who had first-degree relatives with cancer and 2.16 for HL survivors who did not have any first-degree relatives with cancer.

The researchers said the increased risk of second malignancy was correlated with the number of first-degree relatives with cancer.

The SIR was 2.67 for HL patients who had a single first-degree relative with cancer and 3.40 for HL patients who had 2 or more first-degree relatives with cancer.

The SIRs for different cancer types (for HL patients with at least 1 first-degree relative with cancer and no first-degree relatives with cancer, respectively) were as follows:

• NHL—14.43 vs 7.83
• Leukemia—14.31 vs 6.37
• Squamous cell carcinoma—10.85 vs 4.30
• Lung cancer—11.24 vs 3.39
• Breast cancer—4.36 vs 2.36
• Colorectal cancer—3.71 vs 1.76.

Sex and age

The researchers found significant differences in the SIRs for second cancers between HL patients diagnosed before the age of 35 and those diagnosed after age 35.

For men, the SIRs were:

• All cancers—4.26 for <35, 2.08 for ≥ 35
• Colorectal cancer—4.07 for < 35, 1.73 for ≥35
• Lung cancer—6.16 for < 35, 3.20 for ≥35
• Breast cancer—12.60 for < 35, 4.58 for ≥35
• Squamous cell carcinoma—5.89 for < 35, 3.96 for ≥35
• NHL—15.9 for < 35, 6.93 for ≥35
• Leukemia—12.15 for < 35, 5.57 for ≥35.

For women, the SIRs were:

• All cancers—4.61 for <35, 1.73 for ≥ 35
• Colorectal cancer—1.31 for < 35, 1.65 for ≥35
• Lung cancer—8.84 for < 35, 2.50 for ≥35
• Breast cancer—6.00 for < 35, 1.14 for ≥35
• Squamous cell carcinoma—6.37 for < 35, 4.87 for ≥35
• NHL—6.23 for < 35, 6.55 for ≥35
• Leukemia—10.36 for < 35, 4.51 for ≥35.

“Younger women who have been treated with radiotherapy to the chest for Hodgkin lymphoma are already screened for breast cancer, but our study suggests that we should be looking at ways of monitoring survivors for other forms of cancer too, and potentially offering preventative interventions,” Dr Sud said.

“After patients are cured, they no longer encounter oncologists, so it’s important that other healthcare providers are aware of the increased risk to Hodgkin lymphoma survivors to improve early diagnosis of second cancers.”

Photo by Rhoda Baer

A new study suggests Hodgkin lymphoma (HL) survivors have a high risk of developing a second malignancy, particularly if they have a family history of that malignancy.

The research showed that HL survivors in Sweden were roughly 2.4 times more likely than individuals in the country’s general population to develop a second cancer.

The risk for HL survivors remained high 30 years after treatment, and the risk was even greater in HL survivors who had a family history of specific cancers.

“The vast majority of patients with Hodgkin lymphoma are cured with a combination of chemotherapy and radiotherapy,” said study author Amit Sud, MBChB, of The Institute of Cancer Research, London in the UK.

“Our research has shown that these patients are at substantially increased risk of a second cancer later in life and particularly if they have a family history of cancer.”

Dr Sud and his colleagues described this research in the Journal of Clinical Oncology.

The team analyzed data from the Swedish Family-Cancer Project Database. They identified 9522 HL patients diagnosed between 1965 and 2013. During a median follow-up of 12.6 years, there were 1215 second cancers in 1121 HL patients (12%).

Compared to the general population, the HL patients had a significantly higher risk of all second malignancies, with a standardized incident ratio (SIR) of 2.39 and an absolute excess risk of 71.2 cases per 10,000 person-years.

Cancer types

HL patients had a significantly increased risk of several malignancies. The overall SIRs were as follows:

• NHL—7.99
• Leukemia—6.46
• Connective tissue cancer—5.73
• Thyroid cancer—5.13
• Squamous cell carcinoma—4.44
• Lung cancer—3.61
• Pharyngeal cancer—3.52
• Esophageal cancer—2.62
• Brain cancer—2.58
• Breast cancer—2.52
• Colon cancer—2.21
• Pancreatic cancer—2.09
• Melanoma—2.08
• Colorectal cancer—1.85
• Stomach cancer—1.78
• Bladder cancer—1.57
• Prostate cancer—1.21.

The researchers calculated SIRs over time and found the risk for many of the cancers remained high over 30 years following HL treatment.

Family history

The researchers identified 28,277 first-degree relatives of the HL survivors. Thirty percent of HL survivors (n=2785) had 1 or more first-degree relatives with a family history of cancer.

The SIR for cancers was 1.02 in the relatives. The SIR for second cancers was 2.83 for HL survivors who had first-degree relatives with cancer and 2.16 for HL survivors who did not have any first-degree relatives with cancer.

The researchers said the increased risk of second malignancy was correlated with the number of first-degree relatives with cancer.

The SIR was 2.67 for HL patients who had a single first-degree relative with cancer and 3.40 for HL patients who had 2 or more first-degree relatives with cancer.

The SIRs for different cancer types (for HL patients with at least 1 first-degree relative with cancer and no first-degree relatives with cancer, respectively) were as follows:

• NHL—14.43 vs 7.83
• Leukemia—14.31 vs 6.37
• Squamous cell carcinoma—10.85 vs 4.30
• Lung cancer—11.24 vs 3.39
• Breast cancer—4.36 vs 2.36
• Colorectal cancer—3.71 vs 1.76.

Sex and age

The researchers found significant differences in the SIRs for second cancers between HL patients diagnosed before the age of 35 and those diagnosed after age 35.

For men, the SIRs were:

• All cancers—4.26 for <35, 2.08 for ≥ 35
• Colorectal cancer—4.07 for < 35, 1.73 for ≥35
• Lung cancer—6.16 for < 35, 3.20 for ≥35
• Breast cancer—12.60 for < 35, 4.58 for ≥35
• Squamous cell carcinoma—5.89 for < 35, 3.96 for ≥35
• NHL—15.9 for < 35, 6.93 for ≥35
• Leukemia—12.15 for < 35, 5.57 for ≥35.

For women, the SIRs were:

• All cancers—4.61 for <35, 1.73 for ≥ 35
• Colorectal cancer—1.31 for < 35, 1.65 for ≥35
• Lung cancer—8.84 for < 35, 2.50 for ≥35
• Breast cancer—6.00 for < 35, 1.14 for ≥35
• Squamous cell carcinoma—6.37 for < 35, 4.87 for ≥35
• NHL—6.23 for < 35, 6.55 for ≥35
• Leukemia—10.36 for < 35, 4.51 for ≥35.

“Younger women who have been treated with radiotherapy to the chest for Hodgkin lymphoma are already screened for breast cancer, but our study suggests that we should be looking at ways of monitoring survivors for other forms of cancer too, and potentially offering preventative interventions,” Dr Sud said.

“After patients are cured, they no longer encounter oncologists, so it’s important that other healthcare providers are aware of the increased risk to Hodgkin lymphoma survivors to improve early diagnosis of second cancers.”

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has placed a partial clinical hold on all trials of selinexor (KPT-330).

Selinexor is an inhibitor being evaluated in multiple trials of patients with relapsed and/or refractory hematologic and solid tumor malignancies.

While the partial clinical hold remains in effect, patients with stable disease or better may remain on selinexor.

However, no new patients may be enrolled in selinexor trials until the hold is lifted.

The FDA has indicated that the partial clinical hold is due to incomplete information in the existing version of the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.

Karyopharm Therapeutics Inc., the company developing selinexor, said it has amended the brochure, updated the informed consent documents accordingly, and submitted the documents to the FDA as requested.

As of March 10, Karyopharm had provided all requested materials to the FDA believed to be required to lift the partial clinical hold.  By regulation, the FDA has 30 days from the receipt of Karyopharm’s submission to notify the company whether the partial clinical hold is lifted.

Karyopharm said it is working with the FDA to seek the release of the hold and resume enrollment in its selinexor trials as expeditiously as possible. The company believes its previously disclosed enrollment rates and timelines for its ongoing trials will remain materially unchanged.

About selinexor

Selinexor is a selective inhibitor of nuclear export (SINE) XPO1 antagonist. The drug binds with and inhibits XPO1, leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to induce apoptosis in cancer cells while largely sparing normal cells.

To date, more than 1900 patients have been treated with selinexor. The drug is currently being evaluated in several trials across multiple cancer indications.

One of these is the phase 2 SOPRA trial, in which selinexor is being compared to investigator’s choice of therapy (1 of 3 potential salvage therapies). The trial is enrolling patients 60 years of age or older with relapsed or refractory acute myeloid leukemia who are ineligible for standard intensive chemotherapy and/or transplant.

The SADAL study is a phase 2b trial comparing high and low doses of selinexor in patients with relapsed and/or refractory de novo diffuse large B-cell lymphoma who have no therapeutic options of demonstrated clinical benefit.

STORM is a phase 2b trial evaluating selinexor and low-dose dexamethasone in patients with heavily pretreated multiple myeloma (MM). And STOMP is a phase 1b/2 study evaluating selinexor in combination with existing therapies across the broader population in MM.

Karyopharm is also planning a randomized, phase 3 study known as BOSTON. In this trial, researchers will compare selinexor plus bortezomib and low-dose dexamethasone to bortezomib and low-dose dexamethasone in MM patients who have had 1 to 3 prior lines of therapy.

Additional phase 1, 2, and 3 studies are ongoing or currently planned. 

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has placed a partial clinical hold on all trials of selinexor (KPT-330).

Selinexor is an inhibitor being evaluated in multiple trials of patients with relapsed and/or refractory hematologic and solid tumor malignancies.

While the partial clinical hold remains in effect, patients with stable disease or better may remain on selinexor.

However, no new patients may be enrolled in selinexor trials until the hold is lifted.

The FDA has indicated that the partial clinical hold is due to incomplete information in the existing version of the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.

Karyopharm Therapeutics Inc., the company developing selinexor, said it has amended the brochure, updated the informed consent documents accordingly, and submitted the documents to the FDA as requested.

As of March 10, Karyopharm had provided all requested materials to the FDA believed to be required to lift the partial clinical hold.  By regulation, the FDA has 30 days from the receipt of Karyopharm’s submission to notify the company whether the partial clinical hold is lifted.

Karyopharm said it is working with the FDA to seek the release of the hold and resume enrollment in its selinexor trials as expeditiously as possible. The company believes its previously disclosed enrollment rates and timelines for its ongoing trials will remain materially unchanged.

About selinexor

Selinexor is a selective inhibitor of nuclear export (SINE) XPO1 antagonist. The drug binds with and inhibits XPO1, leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to induce apoptosis in cancer cells while largely sparing normal cells.

To date, more than 1900 patients have been treated with selinexor. The drug is currently being evaluated in several trials across multiple cancer indications.

One of these is the phase 2 SOPRA trial, in which selinexor is being compared to investigator’s choice of therapy (1 of 3 potential salvage therapies). The trial is enrolling patients 60 years of age or older with relapsed or refractory acute myeloid leukemia who are ineligible for standard intensive chemotherapy and/or transplant.

The SADAL study is a phase 2b trial comparing high and low doses of selinexor in patients with relapsed and/or refractory de novo diffuse large B-cell lymphoma who have no therapeutic options of demonstrated clinical benefit.

STORM is a phase 2b trial evaluating selinexor and low-dose dexamethasone in patients with heavily pretreated multiple myeloma (MM). And STOMP is a phase 1b/2 study evaluating selinexor in combination with existing therapies across the broader population in MM.

Karyopharm is also planning a randomized, phase 3 study known as BOSTON. In this trial, researchers will compare selinexor plus bortezomib and low-dose dexamethasone to bortezomib and low-dose dexamethasone in MM patients who have had 1 to 3 prior lines of therapy.

Additional phase 1, 2, and 3 studies are ongoing or currently planned. 

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has placed a partial clinical hold on all trials of selinexor (KPT-330).

Selinexor is an inhibitor being evaluated in multiple trials of patients with relapsed and/or refractory hematologic and solid tumor malignancies.

While the partial clinical hold remains in effect, patients with stable disease or better may remain on selinexor.

However, no new patients may be enrolled in selinexor trials until the hold is lifted.

The FDA has indicated that the partial clinical hold is due to incomplete information in the existing version of the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.

Karyopharm Therapeutics Inc., the company developing selinexor, said it has amended the brochure, updated the informed consent documents accordingly, and submitted the documents to the FDA as requested.

As of March 10, Karyopharm had provided all requested materials to the FDA believed to be required to lift the partial clinical hold.  By regulation, the FDA has 30 days from the receipt of Karyopharm’s submission to notify the company whether the partial clinical hold is lifted.

Karyopharm said it is working with the FDA to seek the release of the hold and resume enrollment in its selinexor trials as expeditiously as possible. The company believes its previously disclosed enrollment rates and timelines for its ongoing trials will remain materially unchanged.

About selinexor

Selinexor is a selective inhibitor of nuclear export (SINE) XPO1 antagonist. The drug binds with and inhibits XPO1, leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to induce apoptosis in cancer cells while largely sparing normal cells.

To date, more than 1900 patients have been treated with selinexor. The drug is currently being evaluated in several trials across multiple cancer indications.

One of these is the phase 2 SOPRA trial, in which selinexor is being compared to investigator’s choice of therapy (1 of 3 potential salvage therapies). The trial is enrolling patients 60 years of age or older with relapsed or refractory acute myeloid leukemia who are ineligible for standard intensive chemotherapy and/or transplant.

The SADAL study is a phase 2b trial comparing high and low doses of selinexor in patients with relapsed and/or refractory de novo diffuse large B-cell lymphoma who have no therapeutic options of demonstrated clinical benefit.

STORM is a phase 2b trial evaluating selinexor and low-dose dexamethasone in patients with heavily pretreated multiple myeloma (MM). And STOMP is a phase 1b/2 study evaluating selinexor in combination with existing therapies across the broader population in MM.

Karyopharm is also planning a randomized, phase 3 study known as BOSTON. In this trial, researchers will compare selinexor plus bortezomib and low-dose dexamethasone to bortezomib and low-dose dexamethasone in MM patients who have had 1 to 3 prior lines of therapy.

Additional phase 1, 2, and 3 studies are ongoing or currently planned. 

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan drug designation for eFT508 to treat diffuse large B-cell lymphoma (DLBCL).

eFT508 is a highly selective inhibitor of MNK1 and MNK2, enzymes that integrate signals from several oncogenic and immune signaling pathways.

The FDA grants orphan designation to drugs or biologics intended to treat a disease or condition affecting fewer than 200,000 patients in the US.

The orphan designation for eFT508 provides several incentives for eFFECTOR Therapeutics, the company developing eFT508.

These incentives include increased access to FDA reviewers to discuss clinical trial designs, the ability to qualify for tax credits for certain clinical research costs, the ability to apply for annual grant funding, a waiver of Prescription Drug User Fee Act filing fees, and the potential for 7 years of US marketing exclusivity if eFT508 is approved.

eFFECTOR has dosed the first subject in a phase 1/2 trial of eFT508 in patients with B-cell hematologic malignancies. The study is designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of eFT508.

eFFECTOR presented preclinical research of eFT508 in DLBCL at the 2015 ASH Annual Meeting. The poster is available for download from the eFFECTOR website.

The researchers reported that eFT508 demonstrated anti-proliferative activity against multiple DLBCL cell lines, including the TMD8, OCI-Ly3, and HBL1 cell lines.

eFT508 also exhibited “significant anti-tumor activity” in mouse models of TMD8 and HBL-1 ABC-DLBCL.

Finally, the researchers found that eFT508 synergized with everolimus, ibrutinib, and venetoclax both in vitro and in vivo.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan drug designation for eFT508 to treat diffuse large B-cell lymphoma (DLBCL).

eFT508 is a highly selective inhibitor of MNK1 and MNK2, enzymes that integrate signals from several oncogenic and immune signaling pathways.

The FDA grants orphan designation to drugs or biologics intended to treat a disease or condition affecting fewer than 200,000 patients in the US.

The orphan designation for eFT508 provides several incentives for eFFECTOR Therapeutics, the company developing eFT508.

These incentives include increased access to FDA reviewers to discuss clinical trial designs, the ability to qualify for tax credits for certain clinical research costs, the ability to apply for annual grant funding, a waiver of Prescription Drug User Fee Act filing fees, and the potential for 7 years of US marketing exclusivity if eFT508 is approved.

eFFECTOR has dosed the first subject in a phase 1/2 trial of eFT508 in patients with B-cell hematologic malignancies. The study is designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of eFT508.

eFFECTOR presented preclinical research of eFT508 in DLBCL at the 2015 ASH Annual Meeting. The poster is available for download from the eFFECTOR website.

The researchers reported that eFT508 demonstrated anti-proliferative activity against multiple DLBCL cell lines, including the TMD8, OCI-Ly3, and HBL1 cell lines.

eFT508 also exhibited “significant anti-tumor activity” in mouse models of TMD8 and HBL-1 ABC-DLBCL.

Finally, the researchers found that eFT508 synergized with everolimus, ibrutinib, and venetoclax both in vitro and in vivo.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan drug designation for eFT508 to treat diffuse large B-cell lymphoma (DLBCL).

eFT508 is a highly selective inhibitor of MNK1 and MNK2, enzymes that integrate signals from several oncogenic and immune signaling pathways.

The FDA grants orphan designation to drugs or biologics intended to treat a disease or condition affecting fewer than 200,000 patients in the US.

The orphan designation for eFT508 provides several incentives for eFFECTOR Therapeutics, the company developing eFT508.

These incentives include increased access to FDA reviewers to discuss clinical trial designs, the ability to qualify for tax credits for certain clinical research costs, the ability to apply for annual grant funding, a waiver of Prescription Drug User Fee Act filing fees, and the potential for 7 years of US marketing exclusivity if eFT508 is approved.

eFFECTOR has dosed the first subject in a phase 1/2 trial of eFT508 in patients with B-cell hematologic malignancies. The study is designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of eFT508.

eFFECTOR presented preclinical research of eFT508 in DLBCL at the 2015 ASH Annual Meeting. The poster is available for download from the eFFECTOR website.

The researchers reported that eFT508 demonstrated anti-proliferative activity against multiple DLBCL cell lines, including the TMD8, OCI-Ly3, and HBL1 cell lines.

eFT508 also exhibited “significant anti-tumor activity” in mouse models of TMD8 and HBL-1 ABC-DLBCL.

Finally, the researchers found that eFT508 synergized with everolimus, ibrutinib, and venetoclax both in vitro and in vivo.

Adipose tissue

ORLANDO, FL—A recently conducted study confirms that survivors of hematopoietic stem cell transplant (HSCT) have increased body fat mass and lower lean mass compared to normal controls. And this is despite having a comparable body mass index (BMI).

Researchers say the abnormalities in adipokine levels—leptin and adiponectin—could provide insight into the mechanisms that contribute to the metabolic syndrome and cardiovascular complications that often develop in HSCT survivors.

Leptin and adiponectin are associated with obesity, insulin secretion, insulin resistance, endothelial function, vascular homeostasis, and atherosclerosis.

“So knowing that there is a dynamic interplay between obesity and insulin resistance and cytokine and adipokine profiles and, ultimately, insulin-resistance syndrome, we sought to evaluate, as part of a larger study, how treatment effects, including high-dose chemotherapy and radiation, alter cytokine profiles as well as obesity and body composition,” said Tyler G. Ketterl, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

Dr Ketterl presented the findings at the 2017 BMT Tandem Meetings as abstract 52.*

Study design

The research team compared 151 HSCT recipients who had survived more than 2 years after transplant with 92 sibling controls.

HSCT survivors were randomly recruited from 2 centers—Fred Hutchinson Cancer Research Center and University of Minnesota Masonic Children’s Hospital—and were younger than 21 years when diagnosed.

The researchers evaluated all participants for body composition, cardiovascular risk factors, and adipokines using anthropomorphic measurements, DXA scans for muscle and fat mass, and laboratory bloodwork.

The team stratified the HSCT survivors by the preparative regimen they had received—total body irradiation (TBI) alone, TBI plus cranial radiation (CRT), and chemotherapy alone.

Study population

Males comprised more than half the study population in each arm, 58% of HSCT survivors and 54% of siblings.

Nine percent and 8% in the HSCT and sibling arms, respectively, were non-white and/or Hispanic, and the mean current ages were 24.0 (range, 10-51) for HSCT survivors and 24.2 (range, 10-48) for siblings.

The survivors’ mean age at diagnosis was 9.1 years (range, 0.4–20.6), their mean age at transplant was 11.2 years (range, 0.6–32.6), and the mean time from transplant to study participation was 13.5 years (range, 2.6–32).

Most patients received a transplant for leukemia—54 (36%) for acute myeloid leukemia, 46 (31%) for acute lymphoblastic leukemia, and 15 (10%) for chronic myeloid leukemia. Thirteen (9%) received transplants for myelodysplastic syndromes, 12 (8%) for Hodgkin lymphoma, and 10 (6%) for non-Hodgkin lymphoma.

A little more than half had TBI (85, 56%) as the preparative regimen, 31 (21%) had TBI plus CRT, and 35 (23%) had chemotherapy only.

About three-quarters (116, 77%) had an allogeneic transplant, and 35 (23%) had an autologous transplant.

Results

Overall, HSCT survivors had significantly lower adiponectin levels than siblings (P<0.001).

Survivors who received TBI with or without CRT had significantly lower adiponectin levels than siblings (P<0.001), while survivors who received chemotherapy alone did not (P=0.42).

Adiponectin is involved in insulin sensitization, hepatoprotective action, antiatherogenic action, protection against the development of diabetes, and regulation of lipid metabolism.

Overall, survivors had significantly higher leptin levels than siblings (P<0.001).

This held true regardless of conditioning regimen, although levels for patients who received chemotherapy only were not as significantly high (P=0.02) as for survivors who received TBI (P<0.001).

Leptin helps increase energy expenditure, decrease appetite and food uptake, modify insulin sensitivity on muscles and liver, prevent ectopic lipid deposition, and regulate immune function.

BMI adjusted for age, sex, and Tanner stage was not significantly different between survivors and siblings, but percent fat mass was significantly higher across all conditioning regimens for survivors compared to siblings (P<0.001).

“And this goes along with previous data,” Dr Ketterl said, “that shows sarcopenic obesity is common amongst transplant survivors.”

The researchers believe these significant differences may provide insight into the underlying risk of developing metabolic syndrome and cardiovascular complications in transplant survivors. 

*Some details in the abstract differ from the presentation.

Adipose tissue

ORLANDO, FL—A recently conducted study confirms that survivors of hematopoietic stem cell transplant (HSCT) have increased body fat mass and lower lean mass compared to normal controls. And this is despite having a comparable body mass index (BMI).

Researchers say the abnormalities in adipokine levels—leptin and adiponectin—could provide insight into the mechanisms that contribute to the metabolic syndrome and cardiovascular complications that often develop in HSCT survivors.

Leptin and adiponectin are associated with obesity, insulin secretion, insulin resistance, endothelial function, vascular homeostasis, and atherosclerosis.

“So knowing that there is a dynamic interplay between obesity and insulin resistance and cytokine and adipokine profiles and, ultimately, insulin-resistance syndrome, we sought to evaluate, as part of a larger study, how treatment effects, including high-dose chemotherapy and radiation, alter cytokine profiles as well as obesity and body composition,” said Tyler G. Ketterl, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

Dr Ketterl presented the findings at the 2017 BMT Tandem Meetings as abstract 52.*

Study design

The research team compared 151 HSCT recipients who had survived more than 2 years after transplant with 92 sibling controls.

HSCT survivors were randomly recruited from 2 centers—Fred Hutchinson Cancer Research Center and University of Minnesota Masonic Children’s Hospital—and were younger than 21 years when diagnosed.

The researchers evaluated all participants for body composition, cardiovascular risk factors, and adipokines using anthropomorphic measurements, DXA scans for muscle and fat mass, and laboratory bloodwork.

The team stratified the HSCT survivors by the preparative regimen they had received—total body irradiation (TBI) alone, TBI plus cranial radiation (CRT), and chemotherapy alone.

Study population

Males comprised more than half the study population in each arm, 58% of HSCT survivors and 54% of siblings.

Nine percent and 8% in the HSCT and sibling arms, respectively, were non-white and/or Hispanic, and the mean current ages were 24.0 (range, 10-51) for HSCT survivors and 24.2 (range, 10-48) for siblings.

The survivors’ mean age at diagnosis was 9.1 years (range, 0.4–20.6), their mean age at transplant was 11.2 years (range, 0.6–32.6), and the mean time from transplant to study participation was 13.5 years (range, 2.6–32).

Most patients received a transplant for leukemia—54 (36%) for acute myeloid leukemia, 46 (31%) for acute lymphoblastic leukemia, and 15 (10%) for chronic myeloid leukemia. Thirteen (9%) received transplants for myelodysplastic syndromes, 12 (8%) for Hodgkin lymphoma, and 10 (6%) for non-Hodgkin lymphoma.

A little more than half had TBI (85, 56%) as the preparative regimen, 31 (21%) had TBI plus CRT, and 35 (23%) had chemotherapy only.

About three-quarters (116, 77%) had an allogeneic transplant, and 35 (23%) had an autologous transplant.

Results

Overall, HSCT survivors had significantly lower adiponectin levels than siblings (P<0.001).

Survivors who received TBI with or without CRT had significantly lower adiponectin levels than siblings (P<0.001), while survivors who received chemotherapy alone did not (P=0.42).

Adiponectin is involved in insulin sensitization, hepatoprotective action, antiatherogenic action, protection against the development of diabetes, and regulation of lipid metabolism.

Overall, survivors had significantly higher leptin levels than siblings (P<0.001).

This held true regardless of conditioning regimen, although levels for patients who received chemotherapy only were not as significantly high (P=0.02) as for survivors who received TBI (P<0.001).

Leptin helps increase energy expenditure, decrease appetite and food uptake, modify insulin sensitivity on muscles and liver, prevent ectopic lipid deposition, and regulate immune function.

BMI adjusted for age, sex, and Tanner stage was not significantly different between survivors and siblings, but percent fat mass was significantly higher across all conditioning regimens for survivors compared to siblings (P<0.001).

“And this goes along with previous data,” Dr Ketterl said, “that shows sarcopenic obesity is common amongst transplant survivors.”

The researchers believe these significant differences may provide insight into the underlying risk of developing metabolic syndrome and cardiovascular complications in transplant survivors. 

*Some details in the abstract differ from the presentation.

Adipose tissue

ORLANDO, FL—A recently conducted study confirms that survivors of hematopoietic stem cell transplant (HSCT) have increased body fat mass and lower lean mass compared to normal controls. And this is despite having a comparable body mass index (BMI).

Researchers say the abnormalities in adipokine levels—leptin and adiponectin—could provide insight into the mechanisms that contribute to the metabolic syndrome and cardiovascular complications that often develop in HSCT survivors.

Leptin and adiponectin are associated with obesity, insulin secretion, insulin resistance, endothelial function, vascular homeostasis, and atherosclerosis.

“So knowing that there is a dynamic interplay between obesity and insulin resistance and cytokine and adipokine profiles and, ultimately, insulin-resistance syndrome, we sought to evaluate, as part of a larger study, how treatment effects, including high-dose chemotherapy and radiation, alter cytokine profiles as well as obesity and body composition,” said Tyler G. Ketterl, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

Dr Ketterl presented the findings at the 2017 BMT Tandem Meetings as abstract 52.*

Study design

The research team compared 151 HSCT recipients who had survived more than 2 years after transplant with 92 sibling controls.

HSCT survivors were randomly recruited from 2 centers—Fred Hutchinson Cancer Research Center and University of Minnesota Masonic Children’s Hospital—and were younger than 21 years when diagnosed.

The researchers evaluated all participants for body composition, cardiovascular risk factors, and adipokines using anthropomorphic measurements, DXA scans for muscle and fat mass, and laboratory bloodwork.

The team stratified the HSCT survivors by the preparative regimen they had received—total body irradiation (TBI) alone, TBI plus cranial radiation (CRT), and chemotherapy alone.

Study population

Males comprised more than half the study population in each arm, 58% of HSCT survivors and 54% of siblings.

Nine percent and 8% in the HSCT and sibling arms, respectively, were non-white and/or Hispanic, and the mean current ages were 24.0 (range, 10-51) for HSCT survivors and 24.2 (range, 10-48) for siblings.

The survivors’ mean age at diagnosis was 9.1 years (range, 0.4–20.6), their mean age at transplant was 11.2 years (range, 0.6–32.6), and the mean time from transplant to study participation was 13.5 years (range, 2.6–32).

Most patients received a transplant for leukemia—54 (36%) for acute myeloid leukemia, 46 (31%) for acute lymphoblastic leukemia, and 15 (10%) for chronic myeloid leukemia. Thirteen (9%) received transplants for myelodysplastic syndromes, 12 (8%) for Hodgkin lymphoma, and 10 (6%) for non-Hodgkin lymphoma.

A little more than half had TBI (85, 56%) as the preparative regimen, 31 (21%) had TBI plus CRT, and 35 (23%) had chemotherapy only.

About three-quarters (116, 77%) had an allogeneic transplant, and 35 (23%) had an autologous transplant.

Results

Overall, HSCT survivors had significantly lower adiponectin levels than siblings (P<0.001).

Survivors who received TBI with or without CRT had significantly lower adiponectin levels than siblings (P<0.001), while survivors who received chemotherapy alone did not (P=0.42).

Adiponectin is involved in insulin sensitization, hepatoprotective action, antiatherogenic action, protection against the development of diabetes, and regulation of lipid metabolism.

Overall, survivors had significantly higher leptin levels than siblings (P<0.001).

This held true regardless of conditioning regimen, although levels for patients who received chemotherapy only were not as significantly high (P=0.02) as for survivors who received TBI (P<0.001).

Leptin helps increase energy expenditure, decrease appetite and food uptake, modify insulin sensitivity on muscles and liver, prevent ectopic lipid deposition, and regulate immune function.

BMI adjusted for age, sex, and Tanner stage was not significantly different between survivors and siblings, but percent fat mass was significantly higher across all conditioning regimens for survivors compared to siblings (P<0.001).

“And this goes along with previous data,” Dr Ketterl said, “that shows sarcopenic obesity is common amongst transplant survivors.”

The researchers believe these significant differences may provide insight into the underlying risk of developing metabolic syndrome and cardiovascular complications in transplant survivors. 

*Some details in the abstract differ from the presentation.

Photo by Larry Young

SAN FRANCISCO—An exploratory study suggests cell-free DNA from peripheral blood may be a viable alternative to tumor DNA for mutational profiling in angioimmunoblastic T-cell lymphoma (AITL).

Investigators sequenced cell-free DNA and tumor DNA collected from 13 patients with AITL and found that, in 85% of cases, there was concordance between the tumor mutational profile and the cell-free DNA mutational profile.

“The cell-free DNA mutational analysis seems to mirror the mutational analysis of the tumor in the majority of cases,” said Neha Mehta-Shah, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“This may be particularly interesting when we don’t have very much tumor DNA available for sequencing, as occurs frequently in this patient population.”

Dr Mehta-Shah presented these findings at the 9th Annual T-cell Lymphoma Forum.

She said the primary objective of this study was to evaluate whether somatic mutation analysis of cell-free DNA for IDH2 correlates with tumor mutational profiling for IDH2.

The secondary objective was to evaluate whether somatic mutational analysis of cell-free DNA mirrors the mutational profile of the tumor.

So Dr Mehta-Shah and her colleagues sequenced various samples from 14 patients with AITL (4 who were newly diagnosed and 10 with relapsed disease).

The investigators compared cell-free DNA obtained from peripheral blood samples with genomic DNA obtained from primary tumor biopsies and with DNA from peripheral blood mononuclear cells (for germline comparison). One of the 14 patients didn’t have tumor tissue available, so 13 patients were included in the analysis.

The team performed targeted next-generation sequencing using Memorial Sloan Kettering Cancer Center’s IMPACT platform, which sequences 410 genes known to be recurrently mutated in cancer.

The investigators observed concordance between the tumor mutational profile and the cell-free DNA profile in 85% of cases (11/13).

Identical alterations in TET2, RHOA, IDH2, DNMT3A, and ROS1 were detected in cell-free DNA from peripheral blood and tumor genomic DNA, with a similar variant allele frequency.

On the other hand, mutational analysis of cell-free DNA obtained from urine samples from 2 of the patients did not correlate with somatic mutations from tumor DNA.

This research also revealed that some samples had multiple mutations in TET2, which are indicative of subclonal populations.

And sequential samples from 2 patients, collected at the start of salvage therapy and at subsequent relapse, showed the disappearance of mutations in RHOA, TET2, and IDH2. This observation has been attributed to clonal evolution and/or changes in overall disease burden.

Photo by Larry Young

SAN FRANCISCO—An exploratory study suggests cell-free DNA from peripheral blood may be a viable alternative to tumor DNA for mutational profiling in angioimmunoblastic T-cell lymphoma (AITL).

Investigators sequenced cell-free DNA and tumor DNA collected from 13 patients with AITL and found that, in 85% of cases, there was concordance between the tumor mutational profile and the cell-free DNA mutational profile.

“The cell-free DNA mutational analysis seems to mirror the mutational analysis of the tumor in the majority of cases,” said Neha Mehta-Shah, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“This may be particularly interesting when we don’t have very much tumor DNA available for sequencing, as occurs frequently in this patient population.”

Dr Mehta-Shah presented these findings at the 9th Annual T-cell Lymphoma Forum.

She said the primary objective of this study was to evaluate whether somatic mutation analysis of cell-free DNA for IDH2 correlates with tumor mutational profiling for IDH2.

The secondary objective was to evaluate whether somatic mutational analysis of cell-free DNA mirrors the mutational profile of the tumor.

So Dr Mehta-Shah and her colleagues sequenced various samples from 14 patients with AITL (4 who were newly diagnosed and 10 with relapsed disease).

The investigators compared cell-free DNA obtained from peripheral blood samples with genomic DNA obtained from primary tumor biopsies and with DNA from peripheral blood mononuclear cells (for germline comparison). One of the 14 patients didn’t have tumor tissue available, so 13 patients were included in the analysis.

The team performed targeted next-generation sequencing using Memorial Sloan Kettering Cancer Center’s IMPACT platform, which sequences 410 genes known to be recurrently mutated in cancer.

The investigators observed concordance between the tumor mutational profile and the cell-free DNA profile in 85% of cases (11/13).

Identical alterations in TET2, RHOA, IDH2, DNMT3A, and ROS1 were detected in cell-free DNA from peripheral blood and tumor genomic DNA, with a similar variant allele frequency.

On the other hand, mutational analysis of cell-free DNA obtained from urine samples from 2 of the patients did not correlate with somatic mutations from tumor DNA.

This research also revealed that some samples had multiple mutations in TET2, which are indicative of subclonal populations.

And sequential samples from 2 patients, collected at the start of salvage therapy and at subsequent relapse, showed the disappearance of mutations in RHOA, TET2, and IDH2. This observation has been attributed to clonal evolution and/or changes in overall disease burden.

Photo by Larry Young

SAN FRANCISCO—An exploratory study suggests cell-free DNA from peripheral blood may be a viable alternative to tumor DNA for mutational profiling in angioimmunoblastic T-cell lymphoma (AITL).

Investigators sequenced cell-free DNA and tumor DNA collected from 13 patients with AITL and found that, in 85% of cases, there was concordance between the tumor mutational profile and the cell-free DNA mutational profile.

“The cell-free DNA mutational analysis seems to mirror the mutational analysis of the tumor in the majority of cases,” said Neha Mehta-Shah, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“This may be particularly interesting when we don’t have very much tumor DNA available for sequencing, as occurs frequently in this patient population.”

Dr Mehta-Shah presented these findings at the 9th Annual T-cell Lymphoma Forum.

She said the primary objective of this study was to evaluate whether somatic mutation analysis of cell-free DNA for IDH2 correlates with tumor mutational profiling for IDH2.

The secondary objective was to evaluate whether somatic mutational analysis of cell-free DNA mirrors the mutational profile of the tumor.

So Dr Mehta-Shah and her colleagues sequenced various samples from 14 patients with AITL (4 who were newly diagnosed and 10 with relapsed disease).

The investigators compared cell-free DNA obtained from peripheral blood samples with genomic DNA obtained from primary tumor biopsies and with DNA from peripheral blood mononuclear cells (for germline comparison). One of the 14 patients didn’t have tumor tissue available, so 13 patients were included in the analysis.

The team performed targeted next-generation sequencing using Memorial Sloan Kettering Cancer Center’s IMPACT platform, which sequences 410 genes known to be recurrently mutated in cancer.

The investigators observed concordance between the tumor mutational profile and the cell-free DNA profile in 85% of cases (11/13).

Identical alterations in TET2, RHOA, IDH2, DNMT3A, and ROS1 were detected in cell-free DNA from peripheral blood and tumor genomic DNA, with a similar variant allele frequency.

On the other hand, mutational analysis of cell-free DNA obtained from urine samples from 2 of the patients did not correlate with somatic mutations from tumor DNA.

This research also revealed that some samples had multiple mutations in TET2, which are indicative of subclonal populations.

And sequential samples from 2 patients, collected at the start of salvage therapy and at subsequent relapse, showed the disappearance of mutations in RHOA, TET2, and IDH2. This observation has been attributed to clonal evolution and/or changes in overall disease burden.

mycosis fungoides

The European Commission has granted marketing authorization for chlormethine gel (Ledaga^®) as a treatment for adults with mycosis fungoides (MF), but the product is not expected to be available until next year.

Ledaga is a hybrid medicine of Caryolysine, which has been approved for use in the European Union since 1946.

Hybrid medicines have a different strength, are administered differently, or have a different indication from the reference medicine.

Ledaga contains the same active substance as Caryolysine—chlormethine, a bifunctional alkylating agent that inhibits rapidly proliferating cells—but Ledaga is a gel intended for cutaneous use.

Actelion Pharmaceuticals Ltd, the company developing Ledaga, has agreed to fulfill a list of post-approval measures for the product proposed by the European Medicines Agency’s Committee for Medicinal Products for Human Use.

Subject to fulfilling the agreed commitments and achieving market access in various countries, a potential first European launch of Ledaga is not expected before January 2018. When it is launched, Ledaga will be available as a 160 μg/g gel.

Phase 2 study

The authorization of hybrid medicines depends partly on the results of tests on the reference medicine and partly on new data from clinical trials.

The marketing authorization for Ledaga is based, in part, on results of a multicenter, randomized, observer-blinded, active-controlled study of patients with stage I and IIA MF. Results from this phase 2 study were published in JAMA Dermatology.

The study enrolled 260 MF patients who were randomized 1:1 to receive topical treatment with 0.02% chlormethine gel (Ledaga) or compounded control—0.02% chlormethine compounded in Aquaphor^® ointment—once daily for up to 12 months.

A response was defined as at least a 50% improvement in the baseline Composite Assessment of Index Lesion Severity score.

In the intent-to-treat population, 59% (76/130) of patients who received Ledaga achieved a clinical response, compared to 48% (62/130) of patients treated with the compounded control. The rate of complete response was 14% (n=18) and 12% (n=15), respectively.

Patients who were treated for at least 6 months were included in the efficacy-evaluable population. In this population, 77% (69/90) of patients who received Ledaga achieved a clinical response, compared to 59% (56/95) of patients treated with the compounded control. The rate of complete response was 19% (n=17) and 15% (n=14), respectively.

Reductions in mean lesion severity were seen as early as 4 weeks into the study, with further reductions observed with continuing therapy. The time to first confirmed response favored Ledaga.

The most frequent adverse reactions reported with Ledaga were skin-related—dermatitis (55%; eg, skin irritation, erythema, rash, urticaria, skin-burning sensation, skin pain), pruritus (20%), skin infections (12%), skin ulceration and blistering (6%), and skin hyperpigmentation (6%).

No systemic absorption of chlormethine was detected with treatment.

mycosis fungoides

The European Commission has granted marketing authorization for chlormethine gel (Ledaga^®) as a treatment for adults with mycosis fungoides (MF), but the product is not expected to be available until next year.

Ledaga is a hybrid medicine of Caryolysine, which has been approved for use in the European Union since 1946.

Hybrid medicines have a different strength, are administered differently, or have a different indication from the reference medicine.

Ledaga contains the same active substance as Caryolysine—chlormethine, a bifunctional alkylating agent that inhibits rapidly proliferating cells—but Ledaga is a gel intended for cutaneous use.

Actelion Pharmaceuticals Ltd, the company developing Ledaga, has agreed to fulfill a list of post-approval measures for the product proposed by the European Medicines Agency’s Committee for Medicinal Products for Human Use.

Subject to fulfilling the agreed commitments and achieving market access in various countries, a potential first European launch of Ledaga is not expected before January 2018. When it is launched, Ledaga will be available as a 160 μg/g gel.

Phase 2 study

The authorization of hybrid medicines depends partly on the results of tests on the reference medicine and partly on new data from clinical trials.

The marketing authorization for Ledaga is based, in part, on results of a multicenter, randomized, observer-blinded, active-controlled study of patients with stage I and IIA MF. Results from this phase 2 study were published in JAMA Dermatology.

The study enrolled 260 MF patients who were randomized 1:1 to receive topical treatment with 0.02% chlormethine gel (Ledaga) or compounded control—0.02% chlormethine compounded in Aquaphor^® ointment—once daily for up to 12 months.

A response was defined as at least a 50% improvement in the baseline Composite Assessment of Index Lesion Severity score.

In the intent-to-treat population, 59% (76/130) of patients who received Ledaga achieved a clinical response, compared to 48% (62/130) of patients treated with the compounded control. The rate of complete response was 14% (n=18) and 12% (n=15), respectively.

Patients who were treated for at least 6 months were included in the efficacy-evaluable population. In this population, 77% (69/90) of patients who received Ledaga achieved a clinical response, compared to 59% (56/95) of patients treated with the compounded control. The rate of complete response was 19% (n=17) and 15% (n=14), respectively.

Reductions in mean lesion severity were seen as early as 4 weeks into the study, with further reductions observed with continuing therapy. The time to first confirmed response favored Ledaga.

The most frequent adverse reactions reported with Ledaga were skin-related—dermatitis (55%; eg, skin irritation, erythema, rash, urticaria, skin-burning sensation, skin pain), pruritus (20%), skin infections (12%), skin ulceration and blistering (6%), and skin hyperpigmentation (6%).

No systemic absorption of chlormethine was detected with treatment.

mycosis fungoides

The European Commission has granted marketing authorization for chlormethine gel (Ledaga^®) as a treatment for adults with mycosis fungoides (MF), but the product is not expected to be available until next year.

Ledaga is a hybrid medicine of Caryolysine, which has been approved for use in the European Union since 1946.

Hybrid medicines have a different strength, are administered differently, or have a different indication from the reference medicine.

Ledaga contains the same active substance as Caryolysine—chlormethine, a bifunctional alkylating agent that inhibits rapidly proliferating cells—but Ledaga is a gel intended for cutaneous use.

Actelion Pharmaceuticals Ltd, the company developing Ledaga, has agreed to fulfill a list of post-approval measures for the product proposed by the European Medicines Agency’s Committee for Medicinal Products for Human Use.

Subject to fulfilling the agreed commitments and achieving market access in various countries, a potential first European launch of Ledaga is not expected before January 2018. When it is launched, Ledaga will be available as a 160 μg/g gel.

Phase 2 study

The authorization of hybrid medicines depends partly on the results of tests on the reference medicine and partly on new data from clinical trials.

The marketing authorization for Ledaga is based, in part, on results of a multicenter, randomized, observer-blinded, active-controlled study of patients with stage I and IIA MF. Results from this phase 2 study were published in JAMA Dermatology.

The study enrolled 260 MF patients who were randomized 1:1 to receive topical treatment with 0.02% chlormethine gel (Ledaga) or compounded control—0.02% chlormethine compounded in Aquaphor^® ointment—once daily for up to 12 months.

A response was defined as at least a 50% improvement in the baseline Composite Assessment of Index Lesion Severity score.

In the intent-to-treat population, 59% (76/130) of patients who received Ledaga achieved a clinical response, compared to 48% (62/130) of patients treated with the compounded control. The rate of complete response was 14% (n=18) and 12% (n=15), respectively.

Patients who were treated for at least 6 months were included in the efficacy-evaluable population. In this population, 77% (69/90) of patients who received Ledaga achieved a clinical response, compared to 59% (56/95) of patients treated with the compounded control. The rate of complete response was 19% (n=17) and 15% (n=14), respectively.

Reductions in mean lesion severity were seen as early as 4 weeks into the study, with further reductions observed with continuing therapy. The time to first confirmed response favored Ledaga.

The most frequent adverse reactions reported with Ledaga were skin-related—dermatitis (55%; eg, skin irritation, erythema, rash, urticaria, skin-burning sensation, skin pain), pruritus (20%), skin infections (12%), skin ulceration and blistering (6%), and skin hyperpigmentation (6%).

No systemic absorption of chlormethine was detected with treatment.

Photo by Larry Young

SAN FRANCISCO—A small study suggests an abnormal immune response characterized by the production of interleukin-13 (IL-13) underlies the pathogenesis of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).

The immune response appears to be directed toward bacterial antigens on the surface of the breast implants.

Marshall E. Kadin, MD, of Roger Williams Medical Center in Providence, Rhode Island, presented these findings at the 9th Annual T-cell Lymphoma Forum.

Dr Kadin noted that BIA-ALCL is a rare type of CD30+ T-cell ALCL that has been reported in more than 200 women worldwide.

Although a cause-and-effect relationship between breast implants and BIA-ALCL has been suggested, the underlying pathogenesis of this malignancy is unclear.

A bacterial biofilm containing gram-negative bacilli has been detected in breast implants from patients with BIA-ALCL.

Therefore, Dr Kadin and his colleagues hypothesized that an immune response toward the bacterial antigens may mediate the pathogenesis of BIA-ALCL.

The researchers studied 13 clinical samples of breast implant capsules and regional lymph nodes from 4 patients with BIA-ALCL, 7 patients with systemic ALCL, and 1 patient with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).

Immunohistochemistry was used to determine the presence of IL-13, IL-4, GATA3, and immunoglobulin E (IgE) in these samples.

All clinical samples of anaplastic cells from breast implant capsules tested positive for the presence of IL-13 (13/13). GATA3 was expressed in most anaplastic cell samples (12/13), and IL-4 expression was found in some anaplastic cell samples (6/13). IL-13 and GATA3 expression were observed in some intra-capsular small lymphocytes.

While IL-13 was also detected in BIA-ALCL cell lines, it was not found in 4 of the 7 systemic ALCL cases or the PTCL-NOS case.

Dr Kadin said the lack of IL-13 receptor expression in BIA-ALCL cell lines suggests that IL-13 is not an autocrine growth factor for BIA-ALCL, and its expression is most likely associated with an allergic immune response.

IL-13 is known to induce immunoglobulin class switching in plasma cells to produce IgE. H&E and Giemsa staining of the BIA-ALCL tumor tissue and involved regional lymph nodes revealed IgE and eosinophils on the surface of mast cells and follicular dendritic cells.

Taken together, these data point to an allergic reaction in breast implant capsules of BIA-ALCL.

Dr Kadin was hopeful that these findings could be extrapolated to prevent BIA-ALCL by identifying individuals at higher risk for developing the disease.

The next step for this research is to decipher the role of bacterial antigens in mediating the immune response and whether women who develop BIA-ALCL have a significant increase in other atopic conditions.

Photo by Larry Young

SAN FRANCISCO—A small study suggests an abnormal immune response characterized by the production of interleukin-13 (IL-13) underlies the pathogenesis of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).

The immune response appears to be directed toward bacterial antigens on the surface of the breast implants.

Marshall E. Kadin, MD, of Roger Williams Medical Center in Providence, Rhode Island, presented these findings at the 9th Annual T-cell Lymphoma Forum.

Dr Kadin noted that BIA-ALCL is a rare type of CD30+ T-cell ALCL that has been reported in more than 200 women worldwide.

Although a cause-and-effect relationship between breast implants and BIA-ALCL has been suggested, the underlying pathogenesis of this malignancy is unclear.

A bacterial biofilm containing gram-negative bacilli has been detected in breast implants from patients with BIA-ALCL.

Therefore, Dr Kadin and his colleagues hypothesized that an immune response toward the bacterial antigens may mediate the pathogenesis of BIA-ALCL.

The researchers studied 13 clinical samples of breast implant capsules and regional lymph nodes from 4 patients with BIA-ALCL, 7 patients with systemic ALCL, and 1 patient with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).

Immunohistochemistry was used to determine the presence of IL-13, IL-4, GATA3, and immunoglobulin E (IgE) in these samples.

All clinical samples of anaplastic cells from breast implant capsules tested positive for the presence of IL-13 (13/13). GATA3 was expressed in most anaplastic cell samples (12/13), and IL-4 expression was found in some anaplastic cell samples (6/13). IL-13 and GATA3 expression were observed in some intra-capsular small lymphocytes.

While IL-13 was also detected in BIA-ALCL cell lines, it was not found in 4 of the 7 systemic ALCL cases or the PTCL-NOS case.

Dr Kadin said the lack of IL-13 receptor expression in BIA-ALCL cell lines suggests that IL-13 is not an autocrine growth factor for BIA-ALCL, and its expression is most likely associated with an allergic immune response.

IL-13 is known to induce immunoglobulin class switching in plasma cells to produce IgE. H&E and Giemsa staining of the BIA-ALCL tumor tissue and involved regional lymph nodes revealed IgE and eosinophils on the surface of mast cells and follicular dendritic cells.

Taken together, these data point to an allergic reaction in breast implant capsules of BIA-ALCL.

Dr Kadin was hopeful that these findings could be extrapolated to prevent BIA-ALCL by identifying individuals at higher risk for developing the disease.

The next step for this research is to decipher the role of bacterial antigens in mediating the immune response and whether women who develop BIA-ALCL have a significant increase in other atopic conditions.

Photo by Larry Young

SAN FRANCISCO—A small study suggests an abnormal immune response characterized by the production of interleukin-13 (IL-13) underlies the pathogenesis of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).

The immune response appears to be directed toward bacterial antigens on the surface of the breast implants.

Marshall E. Kadin, MD, of Roger Williams Medical Center in Providence, Rhode Island, presented these findings at the 9th Annual T-cell Lymphoma Forum.

Dr Kadin noted that BIA-ALCL is a rare type of CD30+ T-cell ALCL that has been reported in more than 200 women worldwide.

Although a cause-and-effect relationship between breast implants and BIA-ALCL has been suggested, the underlying pathogenesis of this malignancy is unclear.

A bacterial biofilm containing gram-negative bacilli has been detected in breast implants from patients with BIA-ALCL.

Therefore, Dr Kadin and his colleagues hypothesized that an immune response toward the bacterial antigens may mediate the pathogenesis of BIA-ALCL.

The researchers studied 13 clinical samples of breast implant capsules and regional lymph nodes from 4 patients with BIA-ALCL, 7 patients with systemic ALCL, and 1 patient with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).

Immunohistochemistry was used to determine the presence of IL-13, IL-4, GATA3, and immunoglobulin E (IgE) in these samples.

All clinical samples of anaplastic cells from breast implant capsules tested positive for the presence of IL-13 (13/13). GATA3 was expressed in most anaplastic cell samples (12/13), and IL-4 expression was found in some anaplastic cell samples (6/13). IL-13 and GATA3 expression were observed in some intra-capsular small lymphocytes.

While IL-13 was also detected in BIA-ALCL cell lines, it was not found in 4 of the 7 systemic ALCL cases or the PTCL-NOS case.

Dr Kadin said the lack of IL-13 receptor expression in BIA-ALCL cell lines suggests that IL-13 is not an autocrine growth factor for BIA-ALCL, and its expression is most likely associated with an allergic immune response.

IL-13 is known to induce immunoglobulin class switching in plasma cells to produce IgE. H&E and Giemsa staining of the BIA-ALCL tumor tissue and involved regional lymph nodes revealed IgE and eosinophils on the surface of mast cells and follicular dendritic cells.

Taken together, these data point to an allergic reaction in breast implant capsules of BIA-ALCL.

Dr Kadin was hopeful that these findings could be extrapolated to prevent BIA-ALCL by identifying individuals at higher risk for developing the disease.

The next step for this research is to decipher the role of bacterial antigens in mediating the immune response and whether women who develop BIA-ALCL have a significant increase in other atopic conditions.