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Native Israelis have higher risk of Hodgkin lymphoma
Photo from Hebrew
University of Jerusalem
A study of 2.3 million Jewish subjects suggests that being born in Israel increases a person’s risk of developing Hodgkin lymphoma (HL).
Native Israelis had a higher risk of HL than subjects who immigrated to Israel from Europe, Asia, or North Africa.
Researchers said this finding, published in Leukemia & Lymphoma, suggests that exposure to as-yet-unidentified elements of Israel’s environment increases the risk of HL.
“While we still need further studies to identify the specific causes of the high rates of Hodgkin lymphoma among native Israelis, our findings direct us to search for possible environmental causes in Israel and the neighboring countries,” said study author Hagai Levine, MD, of Hebrew University of Jerusalem in Israel.
“These causes could be not only environmental exposures but also diet, climate, social environment, and stress that may be related to chronic regional conflict.”
Dr Levine and his colleagues noted that the incidence of HL in Israel is among the highest in the world. Based on GLOBOCAN estimates for 2012, Israeli females have the highest age-standardized incidence rate of HL worldwide, and Israeli males have the second highest. From 1960 through 2005, Israel experienced a sharp rise in HL incidence among Israeli-born individuals of both sexes.
Despite evidence for an environmental etiology, very few risk factors have been identified. Studying immigrant populations provides a means of investigating the relative importance of genetic factors as compared to environmental factors in disease development.
With all that in mind, Dr Levine and his colleagues conducted the current study. They included Jewish men and women, ages 16 to 19 at examination, with no history of a cancer diagnosis.
Nationwide data on 2,285,009 adolescents, collected from 1967 through 2011, were linked to Israel’s Cancer Registry to obtain the incidence of HL until 2012.
During 47 million person-years of follow-up, there were 2093 cases of HL detected.
Multivariate analysis suggested native Israelis had a significantly higher risk of developing HL than individuals who immigrated to the country (hazard ratio=1.29, P<0.001). This increased risk was driven largely by an elevated risk for the nodular sclerosis subtype of HL (hazard ratio=1.59, P<0.001).
The researchers noted that the elevated risk appeared within one generation. The low incidence of HL observed for immigrants from Western Asia was no longer evident among Israeli-born individuals of Asian origin. Among immigrants, there was no difference by age at migration.
Therefore, the researchers suggested that immigration from a low-risk to a high-risk location, mostly to locales with a modern lifestyle and environment, is associated with an increase in HL incidence (mainly the nodular sclerosis subtype) within short periods, making genetic drift unlikely as a causal explanation.
On the other hand, the Israeli lifestyle and environment, either independently or by gene-environment interaction, may pose exceptional risks for HL.
“There is increasing evidence for developmental origins of health and disease, with different possible mechanisms, including epigenetic changes or endocrine disruption,” Dr Levine said.
“There is also increasing evidence on the role of prenatal stress in offspring development, including cancer development, especially for hematological malignancies. These data suggest that risk of HL (the nodular sclerosis subtype) is possibly increased due to preconception, prenatal, or early life exposures to a changing lifestyle and environment and its interaction with susceptibility genes.”
Dr Levine and his colleagues also found a higher risk of HL for women, subjects born in more recent years, those with a higher body mass index, and subjects of taller stature. 
Photo from Hebrew
University of Jerusalem
A study of 2.3 million Jewish subjects suggests that being born in Israel increases a person’s risk of developing Hodgkin lymphoma (HL).
Native Israelis had a higher risk of HL than subjects who immigrated to Israel from Europe, Asia, or North Africa.
Researchers said this finding, published in Leukemia & Lymphoma, suggests that exposure to as-yet-unidentified elements of Israel’s environment increases the risk of HL.
“While we still need further studies to identify the specific causes of the high rates of Hodgkin lymphoma among native Israelis, our findings direct us to search for possible environmental causes in Israel and the neighboring countries,” said study author Hagai Levine, MD, of Hebrew University of Jerusalem in Israel.
“These causes could be not only environmental exposures but also diet, climate, social environment, and stress that may be related to chronic regional conflict.”
Dr Levine and his colleagues noted that the incidence of HL in Israel is among the highest in the world. Based on GLOBOCAN estimates for 2012, Israeli females have the highest age-standardized incidence rate of HL worldwide, and Israeli males have the second highest. From 1960 through 2005, Israel experienced a sharp rise in HL incidence among Israeli-born individuals of both sexes.
Despite evidence for an environmental etiology, very few risk factors have been identified. Studying immigrant populations provides a means of investigating the relative importance of genetic factors as compared to environmental factors in disease development.
With all that in mind, Dr Levine and his colleagues conducted the current study. They included Jewish men and women, ages 16 to 19 at examination, with no history of a cancer diagnosis.
Nationwide data on 2,285,009 adolescents, collected from 1967 through 2011, were linked to Israel’s Cancer Registry to obtain the incidence of HL until 2012.
During 47 million person-years of follow-up, there were 2093 cases of HL detected.
Multivariate analysis suggested native Israelis had a significantly higher risk of developing HL than individuals who immigrated to the country (hazard ratio=1.29, P<0.001). This increased risk was driven largely by an elevated risk for the nodular sclerosis subtype of HL (hazard ratio=1.59, P<0.001).
The researchers noted that the elevated risk appeared within one generation. The low incidence of HL observed for immigrants from Western Asia was no longer evident among Israeli-born individuals of Asian origin. Among immigrants, there was no difference by age at migration.
Therefore, the researchers suggested that immigration from a low-risk to a high-risk location, mostly to locales with a modern lifestyle and environment, is associated with an increase in HL incidence (mainly the nodular sclerosis subtype) within short periods, making genetic drift unlikely as a causal explanation.
On the other hand, the Israeli lifestyle and environment, either independently or by gene-environment interaction, may pose exceptional risks for HL.
“There is increasing evidence for developmental origins of health and disease, with different possible mechanisms, including epigenetic changes or endocrine disruption,” Dr Levine said.
“There is also increasing evidence on the role of prenatal stress in offspring development, including cancer development, especially for hematological malignancies. These data suggest that risk of HL (the nodular sclerosis subtype) is possibly increased due to preconception, prenatal, or early life exposures to a changing lifestyle and environment and its interaction with susceptibility genes.”
Dr Levine and his colleagues also found a higher risk of HL for women, subjects born in more recent years, those with a higher body mass index, and subjects of taller stature.
Photo from Hebrew
University of Jerusalem
A study of 2.3 million Jewish subjects suggests that being born in Israel increases a person’s risk of developing Hodgkin lymphoma (HL).
Native Israelis had a higher risk of HL than subjects who immigrated to Israel from Europe, Asia, or North Africa.
Researchers said this finding, published in Leukemia & Lymphoma, suggests that exposure to as-yet-unidentified elements of Israel’s environment increases the risk of HL.
“While we still need further studies to identify the specific causes of the high rates of Hodgkin lymphoma among native Israelis, our findings direct us to search for possible environmental causes in Israel and the neighboring countries,” said study author Hagai Levine, MD, of Hebrew University of Jerusalem in Israel.
“These causes could be not only environmental exposures but also diet, climate, social environment, and stress that may be related to chronic regional conflict.”
Dr Levine and his colleagues noted that the incidence of HL in Israel is among the highest in the world. Based on GLOBOCAN estimates for 2012, Israeli females have the highest age-standardized incidence rate of HL worldwide, and Israeli males have the second highest. From 1960 through 2005, Israel experienced a sharp rise in HL incidence among Israeli-born individuals of both sexes.
Despite evidence for an environmental etiology, very few risk factors have been identified. Studying immigrant populations provides a means of investigating the relative importance of genetic factors as compared to environmental factors in disease development.
With all that in mind, Dr Levine and his colleagues conducted the current study. They included Jewish men and women, ages 16 to 19 at examination, with no history of a cancer diagnosis.
Nationwide data on 2,285,009 adolescents, collected from 1967 through 2011, were linked to Israel’s Cancer Registry to obtain the incidence of HL until 2012.
During 47 million person-years of follow-up, there were 2093 cases of HL detected.
Multivariate analysis suggested native Israelis had a significantly higher risk of developing HL than individuals who immigrated to the country (hazard ratio=1.29, P<0.001). This increased risk was driven largely by an elevated risk for the nodular sclerosis subtype of HL (hazard ratio=1.59, P<0.001).
The researchers noted that the elevated risk appeared within one generation. The low incidence of HL observed for immigrants from Western Asia was no longer evident among Israeli-born individuals of Asian origin. Among immigrants, there was no difference by age at migration.
Therefore, the researchers suggested that immigration from a low-risk to a high-risk location, mostly to locales with a modern lifestyle and environment, is associated with an increase in HL incidence (mainly the nodular sclerosis subtype) within short periods, making genetic drift unlikely as a causal explanation.
On the other hand, the Israeli lifestyle and environment, either independently or by gene-environment interaction, may pose exceptional risks for HL.
“There is increasing evidence for developmental origins of health and disease, with different possible mechanisms, including epigenetic changes or endocrine disruption,” Dr Levine said.
“There is also increasing evidence on the role of prenatal stress in offspring development, including cancer development, especially for hematological malignancies. These data suggest that risk of HL (the nodular sclerosis subtype) is possibly increased due to preconception, prenatal, or early life exposures to a changing lifestyle and environment and its interaction with susceptibility genes.”
Dr Levine and his colleagues also found a higher risk of HL for women, subjects born in more recent years, those with a higher body mass index, and subjects of taller stature.
Long-term health burden of Hodgkin lymphoma treatment
Photo courtesy of St. Jude
Children’s Research Hospital
and Seth Dixon
New research has shown that survivors of pediatric Hodgkin lymphoma (HL) are more likely to have chronic cardiovascular conditions than adults who did not have cancer in childhood.
And cardiovascular conditions are more severe among HL survivors than the general population.
Investigators believe this research, published in The Lancet Oncology, should aid efforts to reduce and better manage the late effects of cancer treatment.
For this study, the investigators used a measurement called “cumulative burden” to better capture the distribution and magnitude of chronic disease in childhood cancer survivors.
The metric showed that, by age 50, HL survivors had more than twice as many cardiovascular problems as adults who had not had cancer as children. HL survivors were also 5 times more likely to have severe, life-threatening, or fatal heart conditions.
“With cure rates for pediatric cancer at historic highs, the question becomes, ‘What is the legacy of that cure?’” said study author Nickhill Bhakta, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“We are doing a better job of keeping patients alive, but are we doing a better job at addressing the chronic diseases that are sometimes the price of that cure? Cumulative burden is a new tool for studying chronic illness in childhood cancer survivors or any patient population with significant morbidity, such as diabetes or HIV/AIDS.”
Unlike statistical methods that count health conditions once at diagnosis, cumulative burden tracks individuals’ multiple, recurring treatment-related health conditions.
Dr Bhakta and his colleagues focused on calculating the cumulative burden of cardiovascular disease in 670 pediatric HL survivors. The subjects were at least 18 years old and had survived at least 10 years beyond their cancer diagnoses.
The participants had been assessed for 22 chronic cardiovascular conditions, including heart attacks, hypertension, arrhythmias, and structural heart defects. Investigators used those and other clinical findings to calculate the cumulative burden by tracking the incidence and severity of cardiovascular disease.
The team also determined the cumulative burden for a comparison group of 272 community volunteers who underwent the same health assessments. The volunteers were similar in age and gender to the HL survivors but had no history of childhood cancer.
The analysis showed that the cumulative burden of cardiovascular disease, including severe and life-threatening conditions, was greater among HL survivors at 30 and 50 years of age than among the comparison group. In fact, the cumulative burden of the most serious heart problems, including heart attacks, was similar for 30-year-old HL survivors and 50-year-old community volunteers.
At age 50, 45.5% of HL survivors had developed at least one grade 3-5 cardiovascular condition, compared to 15.7% of the control subjects.
The HL survivors had a cumulative burden of 430.6 grade 1-5 cardiovascular conditions per 100 individuals and 100.8 grade 3-5 cardiovascular conditions per 100 individuals. In comparison, controls had 227.4 grade 1-5 conditions and 17.0 grade 3-5 conditions per 100 individuals.
The investigators noted that severe, chronic heart conditions became more common with age in both groups, but serious problems accumulated more rapidly in HL survivors.
“Survivors tended to have more severe disease across the lifespan and likely need an individualized screening and treatment plan,” Dr Bhakta said.
He added that the results of this study highlight trade-offs to consider in designing future clinical trials. For example, the investigators found that reducing the dose of anthracyclines will lower the rate, but not the severity, of cardiovascular disease in pediatric and young adult HL survivors.
In contrast, lowering the heart radiation dose will not significantly lower the rate of cardiovascular disease, but it will reduce the severity.
“Cumulative burden provides us with a global view of tradeoffs between different treatment late effects that must be considered when designing new interventions,” Dr Bhakta concluded.
Photo courtesy of St. Jude
Children’s Research Hospital
and Seth Dixon
New research has shown that survivors of pediatric Hodgkin lymphoma (HL) are more likely to have chronic cardiovascular conditions than adults who did not have cancer in childhood.
And cardiovascular conditions are more severe among HL survivors than the general population.
Investigators believe this research, published in The Lancet Oncology, should aid efforts to reduce and better manage the late effects of cancer treatment.
For this study, the investigators used a measurement called “cumulative burden” to better capture the distribution and magnitude of chronic disease in childhood cancer survivors.
The metric showed that, by age 50, HL survivors had more than twice as many cardiovascular problems as adults who had not had cancer as children. HL survivors were also 5 times more likely to have severe, life-threatening, or fatal heart conditions.
“With cure rates for pediatric cancer at historic highs, the question becomes, ‘What is the legacy of that cure?’” said study author Nickhill Bhakta, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“We are doing a better job of keeping patients alive, but are we doing a better job at addressing the chronic diseases that are sometimes the price of that cure? Cumulative burden is a new tool for studying chronic illness in childhood cancer survivors or any patient population with significant morbidity, such as diabetes or HIV/AIDS.”
Unlike statistical methods that count health conditions once at diagnosis, cumulative burden tracks individuals’ multiple, recurring treatment-related health conditions.
Dr Bhakta and his colleagues focused on calculating the cumulative burden of cardiovascular disease in 670 pediatric HL survivors. The subjects were at least 18 years old and had survived at least 10 years beyond their cancer diagnoses.
The participants had been assessed for 22 chronic cardiovascular conditions, including heart attacks, hypertension, arrhythmias, and structural heart defects. Investigators used those and other clinical findings to calculate the cumulative burden by tracking the incidence and severity of cardiovascular disease.
The team also determined the cumulative burden for a comparison group of 272 community volunteers who underwent the same health assessments. The volunteers were similar in age and gender to the HL survivors but had no history of childhood cancer.
The analysis showed that the cumulative burden of cardiovascular disease, including severe and life-threatening conditions, was greater among HL survivors at 30 and 50 years of age than among the comparison group. In fact, the cumulative burden of the most serious heart problems, including heart attacks, was similar for 30-year-old HL survivors and 50-year-old community volunteers.
At age 50, 45.5% of HL survivors had developed at least one grade 3-5 cardiovascular condition, compared to 15.7% of the control subjects.
The HL survivors had a cumulative burden of 430.6 grade 1-5 cardiovascular conditions per 100 individuals and 100.8 grade 3-5 cardiovascular conditions per 100 individuals. In comparison, controls had 227.4 grade 1-5 conditions and 17.0 grade 3-5 conditions per 100 individuals.
The investigators noted that severe, chronic heart conditions became more common with age in both groups, but serious problems accumulated more rapidly in HL survivors.
“Survivors tended to have more severe disease across the lifespan and likely need an individualized screening and treatment plan,” Dr Bhakta said.
He added that the results of this study highlight trade-offs to consider in designing future clinical trials. For example, the investigators found that reducing the dose of anthracyclines will lower the rate, but not the severity, of cardiovascular disease in pediatric and young adult HL survivors.
In contrast, lowering the heart radiation dose will not significantly lower the rate of cardiovascular disease, but it will reduce the severity.
“Cumulative burden provides us with a global view of tradeoffs between different treatment late effects that must be considered when designing new interventions,” Dr Bhakta concluded.
Photo courtesy of St. Jude
Children’s Research Hospital
and Seth Dixon
New research has shown that survivors of pediatric Hodgkin lymphoma (HL) are more likely to have chronic cardiovascular conditions than adults who did not have cancer in childhood.
And cardiovascular conditions are more severe among HL survivors than the general population.
Investigators believe this research, published in The Lancet Oncology, should aid efforts to reduce and better manage the late effects of cancer treatment.
For this study, the investigators used a measurement called “cumulative burden” to better capture the distribution and magnitude of chronic disease in childhood cancer survivors.
The metric showed that, by age 50, HL survivors had more than twice as many cardiovascular problems as adults who had not had cancer as children. HL survivors were also 5 times more likely to have severe, life-threatening, or fatal heart conditions.
“With cure rates for pediatric cancer at historic highs, the question becomes, ‘What is the legacy of that cure?’” said study author Nickhill Bhakta, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“We are doing a better job of keeping patients alive, but are we doing a better job at addressing the chronic diseases that are sometimes the price of that cure? Cumulative burden is a new tool for studying chronic illness in childhood cancer survivors or any patient population with significant morbidity, such as diabetes or HIV/AIDS.”
Unlike statistical methods that count health conditions once at diagnosis, cumulative burden tracks individuals’ multiple, recurring treatment-related health conditions.
Dr Bhakta and his colleagues focused on calculating the cumulative burden of cardiovascular disease in 670 pediatric HL survivors. The subjects were at least 18 years old and had survived at least 10 years beyond their cancer diagnoses.
The participants had been assessed for 22 chronic cardiovascular conditions, including heart attacks, hypertension, arrhythmias, and structural heart defects. Investigators used those and other clinical findings to calculate the cumulative burden by tracking the incidence and severity of cardiovascular disease.
The team also determined the cumulative burden for a comparison group of 272 community volunteers who underwent the same health assessments. The volunteers were similar in age and gender to the HL survivors but had no history of childhood cancer.
The analysis showed that the cumulative burden of cardiovascular disease, including severe and life-threatening conditions, was greater among HL survivors at 30 and 50 years of age than among the comparison group. In fact, the cumulative burden of the most serious heart problems, including heart attacks, was similar for 30-year-old HL survivors and 50-year-old community volunteers.
At age 50, 45.5% of HL survivors had developed at least one grade 3-5 cardiovascular condition, compared to 15.7% of the control subjects.
The HL survivors had a cumulative burden of 430.6 grade 1-5 cardiovascular conditions per 100 individuals and 100.8 grade 3-5 cardiovascular conditions per 100 individuals. In comparison, controls had 227.4 grade 1-5 conditions and 17.0 grade 3-5 conditions per 100 individuals.
The investigators noted that severe, chronic heart conditions became more common with age in both groups, but serious problems accumulated more rapidly in HL survivors.
“Survivors tended to have more severe disease across the lifespan and likely need an individualized screening and treatment plan,” Dr Bhakta said.
He added that the results of this study highlight trade-offs to consider in designing future clinical trials. For example, the investigators found that reducing the dose of anthracyclines will lower the rate, but not the severity, of cardiovascular disease in pediatric and young adult HL survivors.
In contrast, lowering the heart radiation dose will not significantly lower the rate of cardiovascular disease, but it will reduce the severity.
“Cumulative burden provides us with a global view of tradeoffs between different treatment late effects that must be considered when designing new interventions,” Dr Bhakta concluded.
EC grants immunotherapy orphan designation
among uninfected cells (blue)
Image courtesy of
Benjamin Chaigne-Delalande
The European Commission (EC) has granted orphan drug designation for CMD-003 (baltaleucel-T) as a treatment for nasal type extranodal NK/T-cell lymphoma and post-transplant lymphoproliferative disorder.
CMD-003 consists of patient-derived T cells that have been activated to kill malignant cells expressing antigens associated with Epstein-Barr virus (EBV).
The T cells specifically target 4 EBV epitopes—LMP1, LMP2, EBNA, and BARF1.
CMD-003 is being developed by Cell Medica and the Baylor College of Medicine, with funding provided, in part, by the Cancer Prevention and Research Institute of Texas.
About orphan designation
Orphan designation from the EC provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity in the European Union if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
CMD-003 also has orphan designation from the US Food and Drug Administration to treat all EBV-associated non-Hodgkin lymphomas.
CMD-003-related research
CMD-003 is currently under investigation in a phase 2 trial, CITADEL, for the treatment of advanced NK/T-cell lymphoma.
Researchers have not published results from any trials of CMD-003, but they have published results with EBV-specific T-cell products related to CMD-003.
In one study, published in the Journal of Clinical Oncology, researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.
Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.
Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission at 3.1 years after treatment.
Their 2-year event-free survival rate was 82%. None of the patients died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.
Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.
The researchers said there were no toxicities that were definitively related to CTL infusion.
One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.
Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.
among uninfected cells (blue)
Image courtesy of
Benjamin Chaigne-Delalande
The European Commission (EC) has granted orphan drug designation for CMD-003 (baltaleucel-T) as a treatment for nasal type extranodal NK/T-cell lymphoma and post-transplant lymphoproliferative disorder.
CMD-003 consists of patient-derived T cells that have been activated to kill malignant cells expressing antigens associated with Epstein-Barr virus (EBV).
The T cells specifically target 4 EBV epitopes—LMP1, LMP2, EBNA, and BARF1.
CMD-003 is being developed by Cell Medica and the Baylor College of Medicine, with funding provided, in part, by the Cancer Prevention and Research Institute of Texas.
About orphan designation
Orphan designation from the EC provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity in the European Union if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
CMD-003 also has orphan designation from the US Food and Drug Administration to treat all EBV-associated non-Hodgkin lymphomas.
CMD-003-related research
CMD-003 is currently under investigation in a phase 2 trial, CITADEL, for the treatment of advanced NK/T-cell lymphoma.
Researchers have not published results from any trials of CMD-003, but they have published results with EBV-specific T-cell products related to CMD-003.
In one study, published in the Journal of Clinical Oncology, researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.
Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.
Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission at 3.1 years after treatment.
Their 2-year event-free survival rate was 82%. None of the patients died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.
Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.
The researchers said there were no toxicities that were definitively related to CTL infusion.
One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.
Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.
among uninfected cells (blue)
Image courtesy of
Benjamin Chaigne-Delalande
The European Commission (EC) has granted orphan drug designation for CMD-003 (baltaleucel-T) as a treatment for nasal type extranodal NK/T-cell lymphoma and post-transplant lymphoproliferative disorder.
CMD-003 consists of patient-derived T cells that have been activated to kill malignant cells expressing antigens associated with Epstein-Barr virus (EBV).
The T cells specifically target 4 EBV epitopes—LMP1, LMP2, EBNA, and BARF1.
CMD-003 is being developed by Cell Medica and the Baylor College of Medicine, with funding provided, in part, by the Cancer Prevention and Research Institute of Texas.
About orphan designation
Orphan designation from the EC provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity in the European Union if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
CMD-003 also has orphan designation from the US Food and Drug Administration to treat all EBV-associated non-Hodgkin lymphomas.
CMD-003-related research
CMD-003 is currently under investigation in a phase 2 trial, CITADEL, for the treatment of advanced NK/T-cell lymphoma.
Researchers have not published results from any trials of CMD-003, but they have published results with EBV-specific T-cell products related to CMD-003.
In one study, published in the Journal of Clinical Oncology, researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.
Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.
Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission at 3.1 years after treatment.
Their 2-year event-free survival rate was 82%. None of the patients died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.
Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.
The researchers said there were no toxicities that were definitively related to CTL infusion.
One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.
Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.
Drug may be curative for certain HL patients
Photo from Business Wire
Five-year follow-up data from a phase 2 trial indicate that a subset of Hodgkin lymphoma (HL) patients who fail autologous stem cell transplant can achieve long-term disease control with single-agent brentuximab vedotin and may potentially be cured.
Thirty-three percent of patients in this trial achieved a complete remission (CR) with brentuximab vedotin, 13% remained in CR for more than 5 years, and 9% remained in CR without receiving a consolidative allogeneic transplant.
These results were published in Blood. The trial was sponsored by Seattle Genetics, Inc. and Takeda Pharmaceutical Company Limited, the companies developing brentuximab vedotin.
“At the time of trial initiation, historical outcomes for Hodgkin lymphoma patients who relapsed after an autologous stem cell transplant were poor, with median post-progression survival of 1.3 years, and the only long-term disease control option for these patients was considered to be an allogeneic stem cell transplant,” said study author Robert Chen, MD, of City of Hope National Medical Center in Duarte, California.
“The median survival of the patients on [brentuximab vedotin] monotherapy in this pivotal phase 2 trial exceeds these historic figures, and I am pleased to see the publication of the final data.”
Dr Chen previously reported results from this trial at the 2010 ASH Annual Meeting.
The single-arm trial, which supported the US approval of brentuximab vedotin in 2011, was conducted in 102 patients with relapsed or refractory classical HL. The patients’ median age was 31 (range, 15-77), they had an ECOG status of 0 or 1, and both genders were represented equally.
The patients had received a median of 3.5 chemotherapy regimens (range, 1-13), 66% had received prior radiation, and all patients had received an autologous transplant. Seventy-one percent of patients were refractory to frontline therapy, and 42% were refractory to their most recent treatment.
The patients received brentuximab vedotin intravenously at 1.8 mg/kg every 21 days for a maximum of 16 cycles.
Results
Thirty-four patients (33%) achieved a CR. At the 5-year follow-up and end of the study, the median duration of response was not reached.
Thirteen of the 34 patients (38%) who achieved a CR remained in remission at study closure. Of these patients, 4 underwent consolidative allogeneic stem cell transplants while in remission, and 9 received no further therapy.
Among the patients who achieved a CR, the estimated 5-year overall survival (OS) rate was 64%, and the estimated 5-year progression-free survival (PFS) rate was 52%.
For the entire study cohort, the median OS was 40.5 months, and the median PFS was 9.3 months. The estimated 5-year OS was 41%, and the estimated 5-year PFS was 22%.
The most common adverse events of any grade were peripheral sensory neuropathy, fatigue, nausea, neutropenia, and diarrhea.
Treatment-emergent peripheral neuropathy occurred in 56 patients (55%). Eighty-eight percent of these patients had an improvement in their symptoms, and 73% had complete resolution of peripheral neuropathy.
Photo from Business Wire
Five-year follow-up data from a phase 2 trial indicate that a subset of Hodgkin lymphoma (HL) patients who fail autologous stem cell transplant can achieve long-term disease control with single-agent brentuximab vedotin and may potentially be cured.
Thirty-three percent of patients in this trial achieved a complete remission (CR) with brentuximab vedotin, 13% remained in CR for more than 5 years, and 9% remained in CR without receiving a consolidative allogeneic transplant.
These results were published in Blood. The trial was sponsored by Seattle Genetics, Inc. and Takeda Pharmaceutical Company Limited, the companies developing brentuximab vedotin.
“At the time of trial initiation, historical outcomes for Hodgkin lymphoma patients who relapsed after an autologous stem cell transplant were poor, with median post-progression survival of 1.3 years, and the only long-term disease control option for these patients was considered to be an allogeneic stem cell transplant,” said study author Robert Chen, MD, of City of Hope National Medical Center in Duarte, California.
“The median survival of the patients on [brentuximab vedotin] monotherapy in this pivotal phase 2 trial exceeds these historic figures, and I am pleased to see the publication of the final data.”
Dr Chen previously reported results from this trial at the 2010 ASH Annual Meeting.
The single-arm trial, which supported the US approval of brentuximab vedotin in 2011, was conducted in 102 patients with relapsed or refractory classical HL. The patients’ median age was 31 (range, 15-77), they had an ECOG status of 0 or 1, and both genders were represented equally.
The patients had received a median of 3.5 chemotherapy regimens (range, 1-13), 66% had received prior radiation, and all patients had received an autologous transplant. Seventy-one percent of patients were refractory to frontline therapy, and 42% were refractory to their most recent treatment.
The patients received brentuximab vedotin intravenously at 1.8 mg/kg every 21 days for a maximum of 16 cycles.
Results
Thirty-four patients (33%) achieved a CR. At the 5-year follow-up and end of the study, the median duration of response was not reached.
Thirteen of the 34 patients (38%) who achieved a CR remained in remission at study closure. Of these patients, 4 underwent consolidative allogeneic stem cell transplants while in remission, and 9 received no further therapy.
Among the patients who achieved a CR, the estimated 5-year overall survival (OS) rate was 64%, and the estimated 5-year progression-free survival (PFS) rate was 52%.
For the entire study cohort, the median OS was 40.5 months, and the median PFS was 9.3 months. The estimated 5-year OS was 41%, and the estimated 5-year PFS was 22%.
The most common adverse events of any grade were peripheral sensory neuropathy, fatigue, nausea, neutropenia, and diarrhea.
Treatment-emergent peripheral neuropathy occurred in 56 patients (55%). Eighty-eight percent of these patients had an improvement in their symptoms, and 73% had complete resolution of peripheral neuropathy.
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Five-year follow-up data from a phase 2 trial indicate that a subset of Hodgkin lymphoma (HL) patients who fail autologous stem cell transplant can achieve long-term disease control with single-agent brentuximab vedotin and may potentially be cured.
Thirty-three percent of patients in this trial achieved a complete remission (CR) with brentuximab vedotin, 13% remained in CR for more than 5 years, and 9% remained in CR without receiving a consolidative allogeneic transplant.
These results were published in Blood. The trial was sponsored by Seattle Genetics, Inc. and Takeda Pharmaceutical Company Limited, the companies developing brentuximab vedotin.
“At the time of trial initiation, historical outcomes for Hodgkin lymphoma patients who relapsed after an autologous stem cell transplant were poor, with median post-progression survival of 1.3 years, and the only long-term disease control option for these patients was considered to be an allogeneic stem cell transplant,” said study author Robert Chen, MD, of City of Hope National Medical Center in Duarte, California.
“The median survival of the patients on [brentuximab vedotin] monotherapy in this pivotal phase 2 trial exceeds these historic figures, and I am pleased to see the publication of the final data.”
Dr Chen previously reported results from this trial at the 2010 ASH Annual Meeting.
The single-arm trial, which supported the US approval of brentuximab vedotin in 2011, was conducted in 102 patients with relapsed or refractory classical HL. The patients’ median age was 31 (range, 15-77), they had an ECOG status of 0 or 1, and both genders were represented equally.
The patients had received a median of 3.5 chemotherapy regimens (range, 1-13), 66% had received prior radiation, and all patients had received an autologous transplant. Seventy-one percent of patients were refractory to frontline therapy, and 42% were refractory to their most recent treatment.
The patients received brentuximab vedotin intravenously at 1.8 mg/kg every 21 days for a maximum of 16 cycles.
Results
Thirty-four patients (33%) achieved a CR. At the 5-year follow-up and end of the study, the median duration of response was not reached.
Thirteen of the 34 patients (38%) who achieved a CR remained in remission at study closure. Of these patients, 4 underwent consolidative allogeneic stem cell transplants while in remission, and 9 received no further therapy.
Among the patients who achieved a CR, the estimated 5-year overall survival (OS) rate was 64%, and the estimated 5-year progression-free survival (PFS) rate was 52%.
For the entire study cohort, the median OS was 40.5 months, and the median PFS was 9.3 months. The estimated 5-year OS was 41%, and the estimated 5-year PFS was 22%.
The most common adverse events of any grade were peripheral sensory neuropathy, fatigue, nausea, neutropenia, and diarrhea.
Treatment-emergent peripheral neuropathy occurred in 56 patients (55%). Eighty-eight percent of these patients had an improvement in their symptoms, and 73% had complete resolution of peripheral neuropathy.
EC extends marketing authorization for brentuximab vedotin
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The European Commission (EC) has extended the current conditional marketing authorization of brentuximab vedotin (Adcetris) to include the treatment of adults with CD30+ Hodgkin lymphoma (HL) who are at an increased risk of relapse or progression following autologous stem cell transplant (ASCT).
Conditional marketing authorizations are valid for 1 year and are reviewed annually.
The company developing the drug is required to provide comprehensive data confirming the drug’s benefit-risk balance is positive. Once these data are available, the marketing authorization may be converted into a standard marketing authorization.
Drugs are eligible for conditional marketing authorization if they are designated as orphan medicines, intended for use in emergency situations, or designed to treat, prevent, or diagnose seriously debilitating or life-threatening diseases.
The EC previously granted brentuximab vedotin conditional marketing authorization for 2 indications:
- To treat adults with relapsed or refractory CD30+ HL after ASCT or following at least 2 prior therapies when ASCT or multi-agent chemotherapy is not a treatment option
- To treat adults with relapsed or refractory systemic anaplastic large-cell lymphoma (sALCL).
In January 2016, the EC approved a Type II variation to include data on the retreatment of adult patients with HL or sALCL who previously responded to brentuximab vedotin and later relapsed.
Brentuximab vedotin is under joint development by Seattle Genetics and Takeda Pharmaceutical Company Limited.
AETHERA trial
The EC’s decision to extend the conditional marketing authorization of brentuximab vedotin is based on results from the phase 3 AETHERA trial.
The trial was designed to compare brentuximab vedotin to placebo, both administered for up to 16 cycles (approximately 1 year) every 3 weeks following ASCT. Results from the trial were published in The Lancet in March 2015 and presented at the 2014 ASH Annual Meeting.
The study enrolled 329 HL patients at risk of relapse or progression, including 165 on the brentuximab vedotin arm and 164 on the placebo arm.
Patients were eligible for enrollment if they had a history of primary refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-ASCT relapse.
Brentuximab vedotin conferred a significant increase in progression-free survival over placebo, with a hazard ratio of 0.57 (P=0.001). The median progression-free survival was 43 months for patients who received brentuximab vedotin and 24 months for those who received placebo.
The most common adverse events (≥20%), of any grade and regardless of causality, in the brentuximab vedotin arm were neutropenia (78%), peripheral sensory neuropathy (56%), thrombocytopenia (41%), anemia (27%), upper respiratory tract infection (26%), fatigue (24%), peripheral motor neuropathy (23%), nausea (22%), cough (21%), and diarrhea (20%).
The most common adverse events (≥20%), of any grade and regardless of causality, in the placebo arm were neutropenia (34%), upper respiratory tract infection (23%), and thrombocytopenia (20%).
In all, 67% of patients on the brentuximab vedotin arm experienced peripheral neuropathy. Of those patients, 85% had resolution (59%) or partial improvement (26%) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range, 0.1-138).
Photo from Business Wire
The European Commission (EC) has extended the current conditional marketing authorization of brentuximab vedotin (Adcetris) to include the treatment of adults with CD30+ Hodgkin lymphoma (HL) who are at an increased risk of relapse or progression following autologous stem cell transplant (ASCT).
Conditional marketing authorizations are valid for 1 year and are reviewed annually.
The company developing the drug is required to provide comprehensive data confirming the drug’s benefit-risk balance is positive. Once these data are available, the marketing authorization may be converted into a standard marketing authorization.
Drugs are eligible for conditional marketing authorization if they are designated as orphan medicines, intended for use in emergency situations, or designed to treat, prevent, or diagnose seriously debilitating or life-threatening diseases.
The EC previously granted brentuximab vedotin conditional marketing authorization for 2 indications:
- To treat adults with relapsed or refractory CD30+ HL after ASCT or following at least 2 prior therapies when ASCT or multi-agent chemotherapy is not a treatment option
- To treat adults with relapsed or refractory systemic anaplastic large-cell lymphoma (sALCL).
In January 2016, the EC approved a Type II variation to include data on the retreatment of adult patients with HL or sALCL who previously responded to brentuximab vedotin and later relapsed.
Brentuximab vedotin is under joint development by Seattle Genetics and Takeda Pharmaceutical Company Limited.
AETHERA trial
The EC’s decision to extend the conditional marketing authorization of brentuximab vedotin is based on results from the phase 3 AETHERA trial.
The trial was designed to compare brentuximab vedotin to placebo, both administered for up to 16 cycles (approximately 1 year) every 3 weeks following ASCT. Results from the trial were published in The Lancet in March 2015 and presented at the 2014 ASH Annual Meeting.
The study enrolled 329 HL patients at risk of relapse or progression, including 165 on the brentuximab vedotin arm and 164 on the placebo arm.
Patients were eligible for enrollment if they had a history of primary refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-ASCT relapse.
Brentuximab vedotin conferred a significant increase in progression-free survival over placebo, with a hazard ratio of 0.57 (P=0.001). The median progression-free survival was 43 months for patients who received brentuximab vedotin and 24 months for those who received placebo.
The most common adverse events (≥20%), of any grade and regardless of causality, in the brentuximab vedotin arm were neutropenia (78%), peripheral sensory neuropathy (56%), thrombocytopenia (41%), anemia (27%), upper respiratory tract infection (26%), fatigue (24%), peripheral motor neuropathy (23%), nausea (22%), cough (21%), and diarrhea (20%).
The most common adverse events (≥20%), of any grade and regardless of causality, in the placebo arm were neutropenia (34%), upper respiratory tract infection (23%), and thrombocytopenia (20%).
In all, 67% of patients on the brentuximab vedotin arm experienced peripheral neuropathy. Of those patients, 85% had resolution (59%) or partial improvement (26%) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range, 0.1-138).
Photo from Business Wire
The European Commission (EC) has extended the current conditional marketing authorization of brentuximab vedotin (Adcetris) to include the treatment of adults with CD30+ Hodgkin lymphoma (HL) who are at an increased risk of relapse or progression following autologous stem cell transplant (ASCT).
Conditional marketing authorizations are valid for 1 year and are reviewed annually.
The company developing the drug is required to provide comprehensive data confirming the drug’s benefit-risk balance is positive. Once these data are available, the marketing authorization may be converted into a standard marketing authorization.
Drugs are eligible for conditional marketing authorization if they are designated as orphan medicines, intended for use in emergency situations, or designed to treat, prevent, or diagnose seriously debilitating or life-threatening diseases.
The EC previously granted brentuximab vedotin conditional marketing authorization for 2 indications:
- To treat adults with relapsed or refractory CD30+ HL after ASCT or following at least 2 prior therapies when ASCT or multi-agent chemotherapy is not a treatment option
- To treat adults with relapsed or refractory systemic anaplastic large-cell lymphoma (sALCL).
In January 2016, the EC approved a Type II variation to include data on the retreatment of adult patients with HL or sALCL who previously responded to brentuximab vedotin and later relapsed.
Brentuximab vedotin is under joint development by Seattle Genetics and Takeda Pharmaceutical Company Limited.
AETHERA trial
The EC’s decision to extend the conditional marketing authorization of brentuximab vedotin is based on results from the phase 3 AETHERA trial.
The trial was designed to compare brentuximab vedotin to placebo, both administered for up to 16 cycles (approximately 1 year) every 3 weeks following ASCT. Results from the trial were published in The Lancet in March 2015 and presented at the 2014 ASH Annual Meeting.
The study enrolled 329 HL patients at risk of relapse or progression, including 165 on the brentuximab vedotin arm and 164 on the placebo arm.
Patients were eligible for enrollment if they had a history of primary refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-ASCT relapse.
Brentuximab vedotin conferred a significant increase in progression-free survival over placebo, with a hazard ratio of 0.57 (P=0.001). The median progression-free survival was 43 months for patients who received brentuximab vedotin and 24 months for those who received placebo.
The most common adverse events (≥20%), of any grade and regardless of causality, in the brentuximab vedotin arm were neutropenia (78%), peripheral sensory neuropathy (56%), thrombocytopenia (41%), anemia (27%), upper respiratory tract infection (26%), fatigue (24%), peripheral motor neuropathy (23%), nausea (22%), cough (21%), and diarrhea (20%).
The most common adverse events (≥20%), of any grade and regardless of causality, in the placebo arm were neutropenia (34%), upper respiratory tract infection (23%), and thrombocytopenia (20%).
In all, 67% of patients on the brentuximab vedotin arm experienced peripheral neuropathy. Of those patients, 85% had resolution (59%) or partial improvement (26%) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range, 0.1-138).
Pembrolizumab shows signs of efficacy in relapsed/refractory classical Hodgkin lymphoma
PD-1 checkpoint blockade via pembrolizumab is a potential option for classical Hodgkin’s lymphoma that progressed despite brentuximab vedotin therapy, based on a phase Ib, single-arm, open-label, industry-sponsored study of 31 patients.
After a median follow-up of 17 months, five (16%) patients achieved complete remission (90% confidence interval, 7%-31%), and 15 (48%) patients achieved partial remission (90% CI, 33%-64%), for an overall response rate of 65% (48%-79%). Furthermore, 70% of responses lasted at least 24 weeks, reported Philippe Armand, MD, of Dana-Farber Cancer Institute, Boston, and his associates.
“Since the time of study design, it has become apparent that complete responses are not commonly achieved with checkpoint blockade in solid tumors or hematologic malignancies,” they added. “Yet partial responses can be durable, suggesting that the achievement of complete response with checkpoint blockade is not necessary to derive significant clinical benefit.”
Pembrolizumab (Keytruda) is a humanized, highly selective IgG4 anti-PD-1 (programmed death-1) monoclonal antibody approved in the United States for patients with unresectable or metastatic melanoma or metastatic PDL-1 expressing non–small cell lung cancer. Tumor cells in classical Hodgkin lymphoma (HL) often overexpress PD-1 ligands, which “strongly suggests” that HL is PD-1 dependent, the researchers noted (J Clin Oncol. 2016 Jun 27. doi: 10.1200/JCO.2016.67.3467).
The researchers analyzed data for one group of patients within a phase Ib study of pembrolizumab in hematologic malignancies (KEYNOTE-013; NCT01953692). These 31 adults (median age, 32 years; 58% male) all had heavily pretreated classical HL – more than half had received at least five prior lines of therapy, and all had progressed on or after brentuximab vedotin therapy. Most patients (71%) also had received autologous stem cell transplantation. All 31 patients in the study received intravenous pembrolizumab (10 mg/kg) every other week.
Rates of progression-free survival were 69% at 24 weeks and 46% at 52 weeks, the researchers said. “Biomarker analyses demonstrated a high prevalence of PD-L1 and PD-L2 expression, treatment-induced expansion of T cells and natural killer cells, and activation of interferon-gamma, T-cell receptor, and expanded immune-related signaling pathways,” they reported. Those findings indicate that PD-1 blockade activates T-cell and IFN-gamma signaling pathways, which provides “a compelling rationale for the further development of PD-1 blockade in HL,” they concluded.
The most common treatment-related adverse effects were hypothyroidism (16%), diarrhea (16%), nausea (13%), and pneumonitis (10%). Five patients (16%) developed grade 3 treatment-related adverse events, including elevated hepatic transaminases, axillary pain, back pain, joint swelling, colitis, and nephrotic syndrome. Two patients stopped treatment because of adverse effects, but there were no grade 4 events or deaths related to treatment, and no treatment-induced cases of hepatitis, hypophysitis, or uveitis, the researchers noted.
Merck, maker of pembrolizumab, funded the study. Dr. Armand reported financial ties to Merck, Bristol-Myers Squibb, Infinity Pharmaceuticals, Sequenta, Tensha Therapeutics, and Sigma-Tau. Senior author Craig Moskowitz, MD, and five coinvestigators disclosed consulting or advisory relationships or employment with Merck.
PD-1 checkpoint blockade via pembrolizumab is a potential option for classical Hodgkin’s lymphoma that progressed despite brentuximab vedotin therapy, based on a phase Ib, single-arm, open-label, industry-sponsored study of 31 patients.
After a median follow-up of 17 months, five (16%) patients achieved complete remission (90% confidence interval, 7%-31%), and 15 (48%) patients achieved partial remission (90% CI, 33%-64%), for an overall response rate of 65% (48%-79%). Furthermore, 70% of responses lasted at least 24 weeks, reported Philippe Armand, MD, of Dana-Farber Cancer Institute, Boston, and his associates.
“Since the time of study design, it has become apparent that complete responses are not commonly achieved with checkpoint blockade in solid tumors or hematologic malignancies,” they added. “Yet partial responses can be durable, suggesting that the achievement of complete response with checkpoint blockade is not necessary to derive significant clinical benefit.”
Pembrolizumab (Keytruda) is a humanized, highly selective IgG4 anti-PD-1 (programmed death-1) monoclonal antibody approved in the United States for patients with unresectable or metastatic melanoma or metastatic PDL-1 expressing non–small cell lung cancer. Tumor cells in classical Hodgkin lymphoma (HL) often overexpress PD-1 ligands, which “strongly suggests” that HL is PD-1 dependent, the researchers noted (J Clin Oncol. 2016 Jun 27. doi: 10.1200/JCO.2016.67.3467).
The researchers analyzed data for one group of patients within a phase Ib study of pembrolizumab in hematologic malignancies (KEYNOTE-013; NCT01953692). These 31 adults (median age, 32 years; 58% male) all had heavily pretreated classical HL – more than half had received at least five prior lines of therapy, and all had progressed on or after brentuximab vedotin therapy. Most patients (71%) also had received autologous stem cell transplantation. All 31 patients in the study received intravenous pembrolizumab (10 mg/kg) every other week.
Rates of progression-free survival were 69% at 24 weeks and 46% at 52 weeks, the researchers said. “Biomarker analyses demonstrated a high prevalence of PD-L1 and PD-L2 expression, treatment-induced expansion of T cells and natural killer cells, and activation of interferon-gamma, T-cell receptor, and expanded immune-related signaling pathways,” they reported. Those findings indicate that PD-1 blockade activates T-cell and IFN-gamma signaling pathways, which provides “a compelling rationale for the further development of PD-1 blockade in HL,” they concluded.
The most common treatment-related adverse effects were hypothyroidism (16%), diarrhea (16%), nausea (13%), and pneumonitis (10%). Five patients (16%) developed grade 3 treatment-related adverse events, including elevated hepatic transaminases, axillary pain, back pain, joint swelling, colitis, and nephrotic syndrome. Two patients stopped treatment because of adverse effects, but there were no grade 4 events or deaths related to treatment, and no treatment-induced cases of hepatitis, hypophysitis, or uveitis, the researchers noted.
Merck, maker of pembrolizumab, funded the study. Dr. Armand reported financial ties to Merck, Bristol-Myers Squibb, Infinity Pharmaceuticals, Sequenta, Tensha Therapeutics, and Sigma-Tau. Senior author Craig Moskowitz, MD, and five coinvestigators disclosed consulting or advisory relationships or employment with Merck.
PD-1 checkpoint blockade via pembrolizumab is a potential option for classical Hodgkin’s lymphoma that progressed despite brentuximab vedotin therapy, based on a phase Ib, single-arm, open-label, industry-sponsored study of 31 patients.
After a median follow-up of 17 months, five (16%) patients achieved complete remission (90% confidence interval, 7%-31%), and 15 (48%) patients achieved partial remission (90% CI, 33%-64%), for an overall response rate of 65% (48%-79%). Furthermore, 70% of responses lasted at least 24 weeks, reported Philippe Armand, MD, of Dana-Farber Cancer Institute, Boston, and his associates.
“Since the time of study design, it has become apparent that complete responses are not commonly achieved with checkpoint blockade in solid tumors or hematologic malignancies,” they added. “Yet partial responses can be durable, suggesting that the achievement of complete response with checkpoint blockade is not necessary to derive significant clinical benefit.”
Pembrolizumab (Keytruda) is a humanized, highly selective IgG4 anti-PD-1 (programmed death-1) monoclonal antibody approved in the United States for patients with unresectable or metastatic melanoma or metastatic PDL-1 expressing non–small cell lung cancer. Tumor cells in classical Hodgkin lymphoma (HL) often overexpress PD-1 ligands, which “strongly suggests” that HL is PD-1 dependent, the researchers noted (J Clin Oncol. 2016 Jun 27. doi: 10.1200/JCO.2016.67.3467).
The researchers analyzed data for one group of patients within a phase Ib study of pembrolizumab in hematologic malignancies (KEYNOTE-013; NCT01953692). These 31 adults (median age, 32 years; 58% male) all had heavily pretreated classical HL – more than half had received at least five prior lines of therapy, and all had progressed on or after brentuximab vedotin therapy. Most patients (71%) also had received autologous stem cell transplantation. All 31 patients in the study received intravenous pembrolizumab (10 mg/kg) every other week.
Rates of progression-free survival were 69% at 24 weeks and 46% at 52 weeks, the researchers said. “Biomarker analyses demonstrated a high prevalence of PD-L1 and PD-L2 expression, treatment-induced expansion of T cells and natural killer cells, and activation of interferon-gamma, T-cell receptor, and expanded immune-related signaling pathways,” they reported. Those findings indicate that PD-1 blockade activates T-cell and IFN-gamma signaling pathways, which provides “a compelling rationale for the further development of PD-1 blockade in HL,” they concluded.
The most common treatment-related adverse effects were hypothyroidism (16%), diarrhea (16%), nausea (13%), and pneumonitis (10%). Five patients (16%) developed grade 3 treatment-related adverse events, including elevated hepatic transaminases, axillary pain, back pain, joint swelling, colitis, and nephrotic syndrome. Two patients stopped treatment because of adverse effects, but there were no grade 4 events or deaths related to treatment, and no treatment-induced cases of hepatitis, hypophysitis, or uveitis, the researchers noted.
Merck, maker of pembrolizumab, funded the study. Dr. Armand reported financial ties to Merck, Bristol-Myers Squibb, Infinity Pharmaceuticals, Sequenta, Tensha Therapeutics, and Sigma-Tau. Senior author Craig Moskowitz, MD, and five coinvestigators disclosed consulting or advisory relationships or employment with Merck.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Pembrolizumab is a potential treatment option for relapsed/refractory classical Hodgkin lymphoma.
Major finding: The complete response rate was 16%, the overall response rate was 65%, and 70% of responses lasted at least 24 weeks.
Data source: A single-arm, open-label, phase Ib study of pembrolizumab (10 mg/kg every other week) in 31 patients with heavily pretreated classical Hodgkin lymphoma that had progressed on or after brentuximab vedotin.
Disclosures: Merck, maker of pembrolizumab, funded the study. Dr. Armand reported financial ties to Merck, Bristol-Myers Squibb, Infinity Pharmaceuticals, Sequenta, Tensha Therapeutics, and Sigma-Tau. Senior author Craig Moskowitz, MD, and five coinvestigators disclosed consulting or advisory relationships or employment with Merck.
Adding obinutuzumab to bendamustine boosts progression-free survival in rituximab-refractory indolent non-Hodgkin lymphoma
Obinutuzumab and bendamustine followed by obinutuzumab maintenance therapy was superior to bendamustine monotherapy based on progression-free survival in rituximab-refractory patients with indolent non-Hodgkin lymphoma, based on a study published online in the Lancet Oncology.
After a median follow-up of 22 months in the obinutuzumab plus bendamustine group and 20 months in the bendamustine monotherapy group, progression-free survival was significantly longer with obinutuzumab plus bendamustine (median not reached; 95% confidence interval, 22.5 months – not estimable) than with bendamustine monotherapy (14.9 months, range, 12.8-16.6; hazard ratio, 0.55; 95% CI 0.40-0.74; P = .0001). About two-thirds of the nearly 400 patients in both study arms had grade 3-5 adverse events.
The anti-CD20 monoclonal antibody obinutuzumab is an option when patients with indolent non-Hodgkin lymphoma relapse or don’t achieve adequate disease control with rituximab-based treatment, wrote Laurie H. Sehn, MD, of the British Columbia Cancer Agency and the University of British Columbia, Vancouver, and her colleagues.
In an open-label, randomized, phase III study called GADOLIN, patients with CD20-positive indolent non-Hodgkin lymphoma were stratified by indolent non-Hodgkin lymphoma subtype, rituximab-refractory type, number of previous therapies, and geographic region.
For the study, 194 patients were assigned to obinutuzumab plus bendamustine and 202 to bendamustine monotherapy. Trial participants received six 28-day cycles with either obinutuzumab plus bendamustine (obinutuzumab 1,000 mg on days 1, 8, and 15, cycle 1; and on day 1, cycles 2-6) plus bendamustine (90 mg/m2 per day on days 1 and 2, cycles 1-6) or bendamustine monotherapy (120 mg/m2 per day on days 1 and 2 of all cycles). Patients in the obinutuzumab plus bendamustine group whose disease did not progress received obinutuzumab maintenance therapy of 1,000 mg once every 2 months for up to 2 years.
Grade 3-5 adverse events occurred in 68% of 194 patients in the obinutuzumab plus bendamustine group and in 62% of 198 patients in the bendamustine monotherapy group. Grade 3 or worse neutropenia affected 33% of the obinutuzumab plus bendamustine group and 26% of the bendamustine monotherapy group. Other grade 3 or worse events included thrombocytopenia in 11% and 16%, anemia in 8% and 10%, and infusion-related reactions in 11% and 6%. Serious adverse events occurred in 38% in the obinutuzumab plus bendamustine group and in 33% in the bendamustine monotherapy group. Adverse events resulted in death in 6% of patients in each group.
The study was funded by Hoffmann-La Roche. Genentech, the maker of obinutuzumab (Gazyva) in the United States, is a wholly owned member of the Roche Group. Dr. Sehn receives honoraria and is a consultant or advisor to Genentech as well as several other drug companies.
On Twitter @maryjodales
Obinutuzumab and bendamustine followed by obinutuzumab maintenance therapy was superior to bendamustine monotherapy based on progression-free survival in rituximab-refractory patients with indolent non-Hodgkin lymphoma, based on a study published online in the Lancet Oncology.
After a median follow-up of 22 months in the obinutuzumab plus bendamustine group and 20 months in the bendamustine monotherapy group, progression-free survival was significantly longer with obinutuzumab plus bendamustine (median not reached; 95% confidence interval, 22.5 months – not estimable) than with bendamustine monotherapy (14.9 months, range, 12.8-16.6; hazard ratio, 0.55; 95% CI 0.40-0.74; P = .0001). About two-thirds of the nearly 400 patients in both study arms had grade 3-5 adverse events.
The anti-CD20 monoclonal antibody obinutuzumab is an option when patients with indolent non-Hodgkin lymphoma relapse or don’t achieve adequate disease control with rituximab-based treatment, wrote Laurie H. Sehn, MD, of the British Columbia Cancer Agency and the University of British Columbia, Vancouver, and her colleagues.
In an open-label, randomized, phase III study called GADOLIN, patients with CD20-positive indolent non-Hodgkin lymphoma were stratified by indolent non-Hodgkin lymphoma subtype, rituximab-refractory type, number of previous therapies, and geographic region.
For the study, 194 patients were assigned to obinutuzumab plus bendamustine and 202 to bendamustine monotherapy. Trial participants received six 28-day cycles with either obinutuzumab plus bendamustine (obinutuzumab 1,000 mg on days 1, 8, and 15, cycle 1; and on day 1, cycles 2-6) plus bendamustine (90 mg/m2 per day on days 1 and 2, cycles 1-6) or bendamustine monotherapy (120 mg/m2 per day on days 1 and 2 of all cycles). Patients in the obinutuzumab plus bendamustine group whose disease did not progress received obinutuzumab maintenance therapy of 1,000 mg once every 2 months for up to 2 years.
Grade 3-5 adverse events occurred in 68% of 194 patients in the obinutuzumab plus bendamustine group and in 62% of 198 patients in the bendamustine monotherapy group. Grade 3 or worse neutropenia affected 33% of the obinutuzumab plus bendamustine group and 26% of the bendamustine monotherapy group. Other grade 3 or worse events included thrombocytopenia in 11% and 16%, anemia in 8% and 10%, and infusion-related reactions in 11% and 6%. Serious adverse events occurred in 38% in the obinutuzumab plus bendamustine group and in 33% in the bendamustine monotherapy group. Adverse events resulted in death in 6% of patients in each group.
The study was funded by Hoffmann-La Roche. Genentech, the maker of obinutuzumab (Gazyva) in the United States, is a wholly owned member of the Roche Group. Dr. Sehn receives honoraria and is a consultant or advisor to Genentech as well as several other drug companies.
On Twitter @maryjodales
Obinutuzumab and bendamustine followed by obinutuzumab maintenance therapy was superior to bendamustine monotherapy based on progression-free survival in rituximab-refractory patients with indolent non-Hodgkin lymphoma, based on a study published online in the Lancet Oncology.
After a median follow-up of 22 months in the obinutuzumab plus bendamustine group and 20 months in the bendamustine monotherapy group, progression-free survival was significantly longer with obinutuzumab plus bendamustine (median not reached; 95% confidence interval, 22.5 months – not estimable) than with bendamustine monotherapy (14.9 months, range, 12.8-16.6; hazard ratio, 0.55; 95% CI 0.40-0.74; P = .0001). About two-thirds of the nearly 400 patients in both study arms had grade 3-5 adverse events.
The anti-CD20 monoclonal antibody obinutuzumab is an option when patients with indolent non-Hodgkin lymphoma relapse or don’t achieve adequate disease control with rituximab-based treatment, wrote Laurie H. Sehn, MD, of the British Columbia Cancer Agency and the University of British Columbia, Vancouver, and her colleagues.
In an open-label, randomized, phase III study called GADOLIN, patients with CD20-positive indolent non-Hodgkin lymphoma were stratified by indolent non-Hodgkin lymphoma subtype, rituximab-refractory type, number of previous therapies, and geographic region.
For the study, 194 patients were assigned to obinutuzumab plus bendamustine and 202 to bendamustine monotherapy. Trial participants received six 28-day cycles with either obinutuzumab plus bendamustine (obinutuzumab 1,000 mg on days 1, 8, and 15, cycle 1; and on day 1, cycles 2-6) plus bendamustine (90 mg/m2 per day on days 1 and 2, cycles 1-6) or bendamustine monotherapy (120 mg/m2 per day on days 1 and 2 of all cycles). Patients in the obinutuzumab plus bendamustine group whose disease did not progress received obinutuzumab maintenance therapy of 1,000 mg once every 2 months for up to 2 years.
Grade 3-5 adverse events occurred in 68% of 194 patients in the obinutuzumab plus bendamustine group and in 62% of 198 patients in the bendamustine monotherapy group. Grade 3 or worse neutropenia affected 33% of the obinutuzumab plus bendamustine group and 26% of the bendamustine monotherapy group. Other grade 3 or worse events included thrombocytopenia in 11% and 16%, anemia in 8% and 10%, and infusion-related reactions in 11% and 6%. Serious adverse events occurred in 38% in the obinutuzumab plus bendamustine group and in 33% in the bendamustine monotherapy group. Adverse events resulted in death in 6% of patients in each group.
The study was funded by Hoffmann-La Roche. Genentech, the maker of obinutuzumab (Gazyva) in the United States, is a wholly owned member of the Roche Group. Dr. Sehn receives honoraria and is a consultant or advisor to Genentech as well as several other drug companies.
On Twitter @maryjodales
FROM THE LANCET ONCOLOGY
Key clinical point: Obinutuzumab is an option when patients with indolent non-Hodgkin lymphoma relapse or don’t achieve adequate disease control with rituximab-based treatment.
Major finding: Progression-free survival was significantly longer with obinutuzumab plus bendamustine (median not reached; 95% CI, 22.5 months – not estimable) than with bendamustine monotherapy (14.9 months, range,12.8-16.6 months; hazard ratio, 0.55; 95% CI, 0.40-0.74; P = ·0001).
Data source: An open-label, randomized, phase III study of 396 patients.
Disclosures: The study was funded by Hoffmann-La Roche. Genentech, the maker of obinutuzumab (Gazyva) in the United States, is a wholly owned member of the Roche Group. Dr. Sehn receives honoraria and is a consultant or adviser to Genentech as well as several other drug companies.
Interim PET-CT can spare HL patients intensive chemo
The use of interim PET-CT scans can spare some advanced Hodgkin lymphoma (HL) patients the toxicity associated with bleomycin, according to researchers.
The team found that patients with negative PET-CT scans after 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) could go on to receive AVD (doxorubicin, vinblastine, and dacarbazine) without experiencing a significant decrease in progression-free survival (PFS) or overall survival (OS).
Peter Johnson, MD, of the University of Southampton in the UK, and his colleagues reported these findings in NEJM.
“The good news is that the majority of people diagnosed with Hodgkin lymphoma can be cured,” Dr Johnson said. “In this trial, more than 95% of patients are alive after 3 years.”
“But we worry about the long-term side effects from the treatments we use. As we’ve done in this trial, personalizing treatment based on how well it works is a major development for patients with Hodgkin lymphoma and sets a new standard of care.”
Patients and treatment
For this study, Dr Johnson and his colleagues enrolled 1214 patients with newly diagnosed, advanced, classic HL. The patients’ median age was 33 (range, 18 to 79), and 54.5% were male. More patients had stage II disease (41.6%) than stage III (30.2%) or IV (28.3%).
A total of 1119 patients underwent a baseline PET-CT scan, received 2 cycles of ABVD, and underwent an interim PET-CT scan.
The patients with negative interim scans were then randomized to continue treatment with ABVD (n=470) or with AVD (n=465) in cycles 3 through 6.
Patients with positive interim scans (n=182) went on to receive BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, n=172), salvage treatments (n=6), or ABVD (n=4).
Results
The study’s primary outcome was the difference in 3-year PFS between the randomized groups of PET-CT-negative patients.
With a median follow-up of 41 months, the 3-year PFS was 85.7% in the ABVD group and 84.4% in the AVD group. The hazard ratio was 1.13 (95% CI, 0.81 to 1.57; P=0.48) in the intention-to-treat analysis and 1.10 (95% CI, 0.79 to 1.53; P=0.58) in the per-protocol analysis.
The absolute difference in 3-year PFS (ABVD minus AVD) was 1.6 percentage points (95% CI, −3.2 to 5.3).
The OS rates were 97.2% in the ABVD group and 97.6% in the AVD group. The hazard ratio in the intention-to-treat analysis was 0.90 (95% CI, 0.47 to 1.74; P=0.76).
Patients in the ABVD group had a significantly higher rate of clinical adverse events than patients in the AVD group—31% and 21%, respectively (P<0.005).
Patients in the ABVD group also had significantly (P<0.05) higher rates of fatigue (3% vs 1%), febrile neutropenia (5% vs 2%), pulmonary/upper respiratory events (3% vs 1%), and dyspnea (2% vs <0.5%). But patients in the AVD group had a significantly higher rate of thrombocytopenia (3% vs 1%).
For patients who had positive interim PET-CT scans, the 3-year PFS was 67.5%, and the OS was 87.8%. Among the 172 patients who went on to receive BEACOPP, 74.4% had negative findings on a third PET-CT scan.
Overall, 62 patients died during the trial—24 from HL. So, for the entire study cohort, the 3-year PFS was 82.6%, and the OS was 95.8%.
The use of interim PET-CT scans can spare some advanced Hodgkin lymphoma (HL) patients the toxicity associated with bleomycin, according to researchers.
The team found that patients with negative PET-CT scans after 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) could go on to receive AVD (doxorubicin, vinblastine, and dacarbazine) without experiencing a significant decrease in progression-free survival (PFS) or overall survival (OS).
Peter Johnson, MD, of the University of Southampton in the UK, and his colleagues reported these findings in NEJM.
“The good news is that the majority of people diagnosed with Hodgkin lymphoma can be cured,” Dr Johnson said. “In this trial, more than 95% of patients are alive after 3 years.”
“But we worry about the long-term side effects from the treatments we use. As we’ve done in this trial, personalizing treatment based on how well it works is a major development for patients with Hodgkin lymphoma and sets a new standard of care.”
Patients and treatment
For this study, Dr Johnson and his colleagues enrolled 1214 patients with newly diagnosed, advanced, classic HL. The patients’ median age was 33 (range, 18 to 79), and 54.5% were male. More patients had stage II disease (41.6%) than stage III (30.2%) or IV (28.3%).
A total of 1119 patients underwent a baseline PET-CT scan, received 2 cycles of ABVD, and underwent an interim PET-CT scan.
The patients with negative interim scans were then randomized to continue treatment with ABVD (n=470) or with AVD (n=465) in cycles 3 through 6.
Patients with positive interim scans (n=182) went on to receive BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, n=172), salvage treatments (n=6), or ABVD (n=4).
Results
The study’s primary outcome was the difference in 3-year PFS between the randomized groups of PET-CT-negative patients.
With a median follow-up of 41 months, the 3-year PFS was 85.7% in the ABVD group and 84.4% in the AVD group. The hazard ratio was 1.13 (95% CI, 0.81 to 1.57; P=0.48) in the intention-to-treat analysis and 1.10 (95% CI, 0.79 to 1.53; P=0.58) in the per-protocol analysis.
The absolute difference in 3-year PFS (ABVD minus AVD) was 1.6 percentage points (95% CI, −3.2 to 5.3).
The OS rates were 97.2% in the ABVD group and 97.6% in the AVD group. The hazard ratio in the intention-to-treat analysis was 0.90 (95% CI, 0.47 to 1.74; P=0.76).
Patients in the ABVD group had a significantly higher rate of clinical adverse events than patients in the AVD group—31% and 21%, respectively (P<0.005).
Patients in the ABVD group also had significantly (P<0.05) higher rates of fatigue (3% vs 1%), febrile neutropenia (5% vs 2%), pulmonary/upper respiratory events (3% vs 1%), and dyspnea (2% vs <0.5%). But patients in the AVD group had a significantly higher rate of thrombocytopenia (3% vs 1%).
For patients who had positive interim PET-CT scans, the 3-year PFS was 67.5%, and the OS was 87.8%. Among the 172 patients who went on to receive BEACOPP, 74.4% had negative findings on a third PET-CT scan.
Overall, 62 patients died during the trial—24 from HL. So, for the entire study cohort, the 3-year PFS was 82.6%, and the OS was 95.8%.
The use of interim PET-CT scans can spare some advanced Hodgkin lymphoma (HL) patients the toxicity associated with bleomycin, according to researchers.
The team found that patients with negative PET-CT scans after 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) could go on to receive AVD (doxorubicin, vinblastine, and dacarbazine) without experiencing a significant decrease in progression-free survival (PFS) or overall survival (OS).
Peter Johnson, MD, of the University of Southampton in the UK, and his colleagues reported these findings in NEJM.
“The good news is that the majority of people diagnosed with Hodgkin lymphoma can be cured,” Dr Johnson said. “In this trial, more than 95% of patients are alive after 3 years.”
“But we worry about the long-term side effects from the treatments we use. As we’ve done in this trial, personalizing treatment based on how well it works is a major development for patients with Hodgkin lymphoma and sets a new standard of care.”
Patients and treatment
For this study, Dr Johnson and his colleagues enrolled 1214 patients with newly diagnosed, advanced, classic HL. The patients’ median age was 33 (range, 18 to 79), and 54.5% were male. More patients had stage II disease (41.6%) than stage III (30.2%) or IV (28.3%).
A total of 1119 patients underwent a baseline PET-CT scan, received 2 cycles of ABVD, and underwent an interim PET-CT scan.
The patients with negative interim scans were then randomized to continue treatment with ABVD (n=470) or with AVD (n=465) in cycles 3 through 6.
Patients with positive interim scans (n=182) went on to receive BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, n=172), salvage treatments (n=6), or ABVD (n=4).
Results
The study’s primary outcome was the difference in 3-year PFS between the randomized groups of PET-CT-negative patients.
With a median follow-up of 41 months, the 3-year PFS was 85.7% in the ABVD group and 84.4% in the AVD group. The hazard ratio was 1.13 (95% CI, 0.81 to 1.57; P=0.48) in the intention-to-treat analysis and 1.10 (95% CI, 0.79 to 1.53; P=0.58) in the per-protocol analysis.
The absolute difference in 3-year PFS (ABVD minus AVD) was 1.6 percentage points (95% CI, −3.2 to 5.3).
The OS rates were 97.2% in the ABVD group and 97.6% in the AVD group. The hazard ratio in the intention-to-treat analysis was 0.90 (95% CI, 0.47 to 1.74; P=0.76).
Patients in the ABVD group had a significantly higher rate of clinical adverse events than patients in the AVD group—31% and 21%, respectively (P<0.005).
Patients in the ABVD group also had significantly (P<0.05) higher rates of fatigue (3% vs 1%), febrile neutropenia (5% vs 2%), pulmonary/upper respiratory events (3% vs 1%), and dyspnea (2% vs <0.5%). But patients in the AVD group had a significantly higher rate of thrombocytopenia (3% vs 1%).
For patients who had positive interim PET-CT scans, the 3-year PFS was 67.5%, and the OS was 87.8%. Among the 172 patients who went on to receive BEACOPP, 74.4% had negative findings on a third PET-CT scan.
Overall, 62 patients died during the trial—24 from HL. So, for the entire study cohort, the 3-year PFS was 82.6%, and the OS was 95.8%.
Drug can address unmet need in cHL, doc says
COPENHAGEN—The PD-1 checkpoint inhibitor nivolumab can address an unmet need in patients with classical Hodgkin lymphoma (cHL) who have progressive or relapsed disease, according to a speaker at the 21st Congress of the European Hematology Association.
In the phase 2 Checkmate-205 trial, nivolumab produced an objective response rate of 66% in cHL patients who had relapsed or progressed after autologous hematopoietic stem cell transplant (HSCT) and subsequent brentuximab vedotin.
The median duration of response was 7.8 months, and most patients had a response that was ongoing at the time of analysis.
Although the safety profile of nivolumab was considered “acceptable” by researchers, the drug has been linked to serious complications, including death, among patients who proceeded to allogeneic HSCT after receiving nivolumab.
Still, nivolumab is “an important new therapy to meet the unmet need” in cHL, according to Anas Younes, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
Dr Younes presented results with nivolumab from cohort B of the Checkmate-205 trial as abstract S793. Checkmate-205 was sponsored by Bristol-Myers Squibb.
Cohort B included 80 cHL patients who had relapsed or progressed after autologous HSCT and post-transplant brentuximab vedotin. (Cohort A included patients who had not previously received brentuximab vedotin.)
The patients’ median age was 37 (range, 18-72), and 64% were male. The median number of prior lines of therapy was 4 (range, 3-15), and 49% of patients had received at least 5 previous lines of therapy.
Seventy-four percent of patients had previously received radiation, 93% had received 1 prior autologous HSCT, and 8% had received 2. All patients had received brentuximab vedotin after transplant, and 54% had not responded to that treatment.
Study treatment
Patients received nivolumab at 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity.
At a median follow-up of 8.9 months (range, 1.9-11.7), 36% of patients had come off treatment—16% due to disease progression, 5% due to toxicity, 8% because they had gone on to allogeneic HSCT, and 8% for other reasons (the patient’s request, the investigator’s decision, the patient was lost to follow-up, or the reason was not reported).
Dr Younes noted that all patients who stopped nivolumab to undergo HSCT were still alive at the data cut-off.
Efficacy
The objective response rate, per an independent radiologic review committee, was 66%. Nine percent of patients achieved a complete response, 58% had a partial response, 23% had stable disease, and 8% had progressive disease. The committee was unable to determine the status of 4% of patients.
The median time to response was 2.1 months, and the estimated median duration of response was 7.8 months.
“Keep in mind that the majority of patients are still on therapy, so this is expected to improve with time,” Dr Younes said.
The majority of responses (62%) were ongoing at the time of analysis. In an exploratory analysis, the researchers observed that 72% of patients who did not respond to their most recent prior brentuximab vedotin treatment did respond to nivolumab.
At 6 months, the progression-free survival rate was 77%, and the overall survival rate was 99%. The median progression-free survival was 10 months, and the median overall survival has not been reached.
Dr Younes said that, although the follow-up is short, the survival data are “still impressive.”
Safety
Adverse events (AEs) occurred in 99% of patients, grade 3/4 AEs occurred in 40% of patients, and there was 1 grade 5 AE (multi-organ failure due to Epstein-Barr-virus-positive T-cell lymphoma).
Treatment-related AEs occurred in 90% of patients. The most common of these were fatigue (25%), infusion-related reactions (20%), rash (16%), arthralgia (14%), pyrexia (14%), nausea (13%), diarrhea (10%), and pruritus (10%).
Treatment-related serious AEs occurred in 6% of patients and included pyrexia, tumor progression, arrhythmia, infusion reactions, septic meningitis, and pneumonia.
Extended safety follow-up of cHL patients treated in the nivolumab clinical trial program who were subsequently treated with allogeneic HSCT (n=17) revealed complications, including fatal events.
A warning about such complications has been added to the US prescribing information for nivolumab, which was recently granted accelerated approval from the US Food and Drug Administration (FDA) to treat patients with relapsed or refractory cHL who have received an autologous HSCT and post-transplant brentuximab vedotin.
Because of these transplant-related deaths, the FDA has advised that healthcare professionals follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host disease, severe acute graft-versus-host disease, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions.
The FDA has also required that Bristol-Myers Squibb further study the safety of allogeneic HSCT after nivolumab.
COPENHAGEN—The PD-1 checkpoint inhibitor nivolumab can address an unmet need in patients with classical Hodgkin lymphoma (cHL) who have progressive or relapsed disease, according to a speaker at the 21st Congress of the European Hematology Association.
In the phase 2 Checkmate-205 trial, nivolumab produced an objective response rate of 66% in cHL patients who had relapsed or progressed after autologous hematopoietic stem cell transplant (HSCT) and subsequent brentuximab vedotin.
The median duration of response was 7.8 months, and most patients had a response that was ongoing at the time of analysis.
Although the safety profile of nivolumab was considered “acceptable” by researchers, the drug has been linked to serious complications, including death, among patients who proceeded to allogeneic HSCT after receiving nivolumab.
Still, nivolumab is “an important new therapy to meet the unmet need” in cHL, according to Anas Younes, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
Dr Younes presented results with nivolumab from cohort B of the Checkmate-205 trial as abstract S793. Checkmate-205 was sponsored by Bristol-Myers Squibb.
Cohort B included 80 cHL patients who had relapsed or progressed after autologous HSCT and post-transplant brentuximab vedotin. (Cohort A included patients who had not previously received brentuximab vedotin.)
The patients’ median age was 37 (range, 18-72), and 64% were male. The median number of prior lines of therapy was 4 (range, 3-15), and 49% of patients had received at least 5 previous lines of therapy.
Seventy-four percent of patients had previously received radiation, 93% had received 1 prior autologous HSCT, and 8% had received 2. All patients had received brentuximab vedotin after transplant, and 54% had not responded to that treatment.
Study treatment
Patients received nivolumab at 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity.
At a median follow-up of 8.9 months (range, 1.9-11.7), 36% of patients had come off treatment—16% due to disease progression, 5% due to toxicity, 8% because they had gone on to allogeneic HSCT, and 8% for other reasons (the patient’s request, the investigator’s decision, the patient was lost to follow-up, or the reason was not reported).
Dr Younes noted that all patients who stopped nivolumab to undergo HSCT were still alive at the data cut-off.
Efficacy
The objective response rate, per an independent radiologic review committee, was 66%. Nine percent of patients achieved a complete response, 58% had a partial response, 23% had stable disease, and 8% had progressive disease. The committee was unable to determine the status of 4% of patients.
The median time to response was 2.1 months, and the estimated median duration of response was 7.8 months.
“Keep in mind that the majority of patients are still on therapy, so this is expected to improve with time,” Dr Younes said.
The majority of responses (62%) were ongoing at the time of analysis. In an exploratory analysis, the researchers observed that 72% of patients who did not respond to their most recent prior brentuximab vedotin treatment did respond to nivolumab.
At 6 months, the progression-free survival rate was 77%, and the overall survival rate was 99%. The median progression-free survival was 10 months, and the median overall survival has not been reached.
Dr Younes said that, although the follow-up is short, the survival data are “still impressive.”
Safety
Adverse events (AEs) occurred in 99% of patients, grade 3/4 AEs occurred in 40% of patients, and there was 1 grade 5 AE (multi-organ failure due to Epstein-Barr-virus-positive T-cell lymphoma).
Treatment-related AEs occurred in 90% of patients. The most common of these were fatigue (25%), infusion-related reactions (20%), rash (16%), arthralgia (14%), pyrexia (14%), nausea (13%), diarrhea (10%), and pruritus (10%).
Treatment-related serious AEs occurred in 6% of patients and included pyrexia, tumor progression, arrhythmia, infusion reactions, septic meningitis, and pneumonia.
Extended safety follow-up of cHL patients treated in the nivolumab clinical trial program who were subsequently treated with allogeneic HSCT (n=17) revealed complications, including fatal events.
A warning about such complications has been added to the US prescribing information for nivolumab, which was recently granted accelerated approval from the US Food and Drug Administration (FDA) to treat patients with relapsed or refractory cHL who have received an autologous HSCT and post-transplant brentuximab vedotin.
Because of these transplant-related deaths, the FDA has advised that healthcare professionals follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host disease, severe acute graft-versus-host disease, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions.
The FDA has also required that Bristol-Myers Squibb further study the safety of allogeneic HSCT after nivolumab.
COPENHAGEN—The PD-1 checkpoint inhibitor nivolumab can address an unmet need in patients with classical Hodgkin lymphoma (cHL) who have progressive or relapsed disease, according to a speaker at the 21st Congress of the European Hematology Association.
In the phase 2 Checkmate-205 trial, nivolumab produced an objective response rate of 66% in cHL patients who had relapsed or progressed after autologous hematopoietic stem cell transplant (HSCT) and subsequent brentuximab vedotin.
The median duration of response was 7.8 months, and most patients had a response that was ongoing at the time of analysis.
Although the safety profile of nivolumab was considered “acceptable” by researchers, the drug has been linked to serious complications, including death, among patients who proceeded to allogeneic HSCT after receiving nivolumab.
Still, nivolumab is “an important new therapy to meet the unmet need” in cHL, according to Anas Younes, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
Dr Younes presented results with nivolumab from cohort B of the Checkmate-205 trial as abstract S793. Checkmate-205 was sponsored by Bristol-Myers Squibb.
Cohort B included 80 cHL patients who had relapsed or progressed after autologous HSCT and post-transplant brentuximab vedotin. (Cohort A included patients who had not previously received brentuximab vedotin.)
The patients’ median age was 37 (range, 18-72), and 64% were male. The median number of prior lines of therapy was 4 (range, 3-15), and 49% of patients had received at least 5 previous lines of therapy.
Seventy-four percent of patients had previously received radiation, 93% had received 1 prior autologous HSCT, and 8% had received 2. All patients had received brentuximab vedotin after transplant, and 54% had not responded to that treatment.
Study treatment
Patients received nivolumab at 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity.
At a median follow-up of 8.9 months (range, 1.9-11.7), 36% of patients had come off treatment—16% due to disease progression, 5% due to toxicity, 8% because they had gone on to allogeneic HSCT, and 8% for other reasons (the patient’s request, the investigator’s decision, the patient was lost to follow-up, or the reason was not reported).
Dr Younes noted that all patients who stopped nivolumab to undergo HSCT were still alive at the data cut-off.
Efficacy
The objective response rate, per an independent radiologic review committee, was 66%. Nine percent of patients achieved a complete response, 58% had a partial response, 23% had stable disease, and 8% had progressive disease. The committee was unable to determine the status of 4% of patients.
The median time to response was 2.1 months, and the estimated median duration of response was 7.8 months.
“Keep in mind that the majority of patients are still on therapy, so this is expected to improve with time,” Dr Younes said.
The majority of responses (62%) were ongoing at the time of analysis. In an exploratory analysis, the researchers observed that 72% of patients who did not respond to their most recent prior brentuximab vedotin treatment did respond to nivolumab.
At 6 months, the progression-free survival rate was 77%, and the overall survival rate was 99%. The median progression-free survival was 10 months, and the median overall survival has not been reached.
Dr Younes said that, although the follow-up is short, the survival data are “still impressive.”
Safety
Adverse events (AEs) occurred in 99% of patients, grade 3/4 AEs occurred in 40% of patients, and there was 1 grade 5 AE (multi-organ failure due to Epstein-Barr-virus-positive T-cell lymphoma).
Treatment-related AEs occurred in 90% of patients. The most common of these were fatigue (25%), infusion-related reactions (20%), rash (16%), arthralgia (14%), pyrexia (14%), nausea (13%), diarrhea (10%), and pruritus (10%).
Treatment-related serious AEs occurred in 6% of patients and included pyrexia, tumor progression, arrhythmia, infusion reactions, septic meningitis, and pneumonia.
Extended safety follow-up of cHL patients treated in the nivolumab clinical trial program who were subsequently treated with allogeneic HSCT (n=17) revealed complications, including fatal events.
A warning about such complications has been added to the US prescribing information for nivolumab, which was recently granted accelerated approval from the US Food and Drug Administration (FDA) to treat patients with relapsed or refractory cHL who have received an autologous HSCT and post-transplant brentuximab vedotin.
Because of these transplant-related deaths, the FDA has advised that healthcare professionals follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host disease, severe acute graft-versus-host disease, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions.
The FDA has also required that Bristol-Myers Squibb further study the safety of allogeneic HSCT after nivolumab.
HIV not a contraindication for transplant in lymphoma
cultured lymphocyte
Image courtesy of CDC
With the advent of effective anti-retroviral therapy, patients with HIV-related lymphoma receive standard therapeutic regimens and achieve outcomes comparable to those of non-HIV-infected individuals.
Based on results of a multicenter phase 2 study, this now extends to treatment with autologous stem cell transplant (ASCT).
Researchers found that outcomes were not significantly different between HIV-infected patients who received ASCT and matched controls.
“These findings are remarkably important for a group of patients who, up until now, have been inconsistently treated,” said lead study author Joseph C. Alvarnas, MD, of City of Hope National Medical Center in Duarte, California.
“Based on our data, autologous stem cell transplant should be considered the standard of care for patients with HIV-related lymphomas for the same indications and under the same circumstances that we would use it in patients without HIV infection.”
To arrive at this recommendation, investigators enrolled 43 HIV-infected patients with relapsed or persistent non-Hodgkin lymphoma (NHL) or classical Hodgkin lymphoma (HL) onto the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0803/AIDS Malignancy Consortium (AMC) 071 study.
They reported their findings in Blood.
Eligibility
Patients had to be 15 years or older, have documented evidence of HIV infection, and have a Karnofsky performance status of greater than 70%.
They had to have persistent or recurrent diffuse large B-cell lymphoma, immunoblastic lymphoma, plasmablastic lymphoma, Burkitt lymphoma, Burkitt-like NHL, or classic HL.
Patients could have had no more than 3 prior treatment regimens or 2 or fewer salvage regimens.
They had to have adequate organ function, fewer than 10% blasts in their marrow, no prior autologous or allogeneic transplant, and adequate hematopoietic progenitor cell mobilization of more than 1.5 x 106 CD34+ cells/kg to be eligible.
Transplant regimen
Patients received the BEAM (carmustine, etoposide, cytarabine, and melphalan) transplant regimen on day 0. They did not receive antiretroviral therapy from the time of the start of BEAM until 7 days after completion of the preparative regimen.
Efavirenz was held for 2 weeks prior to BEAM initiation, and an alternative agent was substituted during this time period. Zidovudine was prohibited following transplant because of its myelosuppressive effects.
Patients received growth factor, transfusion, and antimicrobial supportive care according to institutional standards of the transplant center.
Patient characteristics
Of the original 43 patients enrolled, 3 patients experienced disease progression prior to the conditioning regimen and did not undergo transplant. Therefore, investigators did not include them in the study analysis.
Forty patients received ASCT at 16 different transplant centers. They were a median age of 46.9 (range, 22.5–62.2), and 35 were male.
All patients received peripheral blood stem cell grafts at a median dose of 3.9 x 106 CD34+ cells/kg (range, 1.6–11.0). And all patients were able to mobilize hematopoietic progenitor cells in a median of 2 apheresis collections (range, 1–5).
Most patients (n=32; 80%) had a pre-transplant HIV viral load that was undetectable. The median viral load for those 8 patients with detectable disease was 80 copies/mL (range, 50–17,455).
Patients had a median pre-transplant CD4+ T-cell count of 249.0 CD4+/μL (range, 39–797).
Investigators followed the patients for a median of 24.8 months (range, 2.8–27.2).
Response
Seven patients died during the follow-up period, 5 within 1 year of transplant. Four of the deaths within 1 year of transplant were due to relapse or disease progression.
One-year transplant-related mortality (TRM) was 5.2%.
The 1-year overall survival (OS) probability was 87.3%, and, at 2 years, it was 82%. The 2-year progression-free survival (PFS) was 79.8%, and the cumulative incidence of relapse/progression at 2 years was 12.5%.
The probabilities for OS and PFS at 2 years were comparable for both NHL and HL patients.
The median time to post-transplant neutrophil recovery was 11 days, and 97.5% of patients recovered their neutrophil counts by day 28.
The median time to platelet recovery was 18 days, and 92.5% of patients recovered their platelet counts by day 100.
At 100 days post-transplant, 28.9% of the evaluable patients (11/38) had recovered hematologic function. And at 1 year, 74.2% (23/31) had recovered hematologic function.
Adverse events
A little more than half (55%) the patients had at least 1 infectious event within a year of transplant, including 11 who had a severe infection.
Of the 57 infections that occurred post-transplant, 25 were due to bacteria, 22 to viruses, 6 to fungal organisms, 2 to protozoa, and 2 to other organisms. No patient developed Pneumocystis jiroveci pneumonia after transplant.
Nine patients experienced a total of 13 grade 3–5 adverse events. This included infection/sepsis (5 events), venous thromboembolism (2 events), and 1 event each for esophageal candidiasis, enteritis, hyperglycemia, hypernatremia, acute appendicitis, and acute coronary syndrome.
Sixteen patients had to be re-admitted to the hospital after the transplant, for a total of 34 readmissions. Infection (18) and fever (6) were the most common reasons for readmission.
Data comparison
The investigators compared the OS and PFS results to a control group identified through the Center for International Bone Marrow Transplant Research (CIBMTR).
One hundred fifty-one controls matched for age, performance status, primary disease, and disease status at transplant were identified for the 40 HIV-lymphoma cases.
The 1-year OS for the control group was 87.7%, and the 2-year PFS was 69.5%. This compared with the 87.3% and 79.8% for OS and PFS, respectively, for the HIV-lymphoma patients.
These results, the investigators wrote, were not significantly different from outcomes of CIBMTR controls, with a hazard ratio for overall mortality in the HIV-lymphoma patients of 0.67 (95% CI: 0.30–1.50, P=0.33) compared to controls.
And the hazard ratio for treatment failure in the HIV-lymphoma patients was 0.52 (95% CI: 0.2927–1.03, P=0.06) compared to controls.
The investigators concluded that HIV infection alone should not be considered a contraindication to ASCT for patients who otherwise meet transplant inclusion criteria. And ASCT should be considered the standard of care for patients with HIV-related lymphoma, provided that the HIV infection is treatment-responsive.
The team added that these patients should also be considered “appropriate potential participants” for future ASCT clinical trials.
cultured lymphocyte
Image courtesy of CDC
With the advent of effective anti-retroviral therapy, patients with HIV-related lymphoma receive standard therapeutic regimens and achieve outcomes comparable to those of non-HIV-infected individuals.
Based on results of a multicenter phase 2 study, this now extends to treatment with autologous stem cell transplant (ASCT).
Researchers found that outcomes were not significantly different between HIV-infected patients who received ASCT and matched controls.
“These findings are remarkably important for a group of patients who, up until now, have been inconsistently treated,” said lead study author Joseph C. Alvarnas, MD, of City of Hope National Medical Center in Duarte, California.
“Based on our data, autologous stem cell transplant should be considered the standard of care for patients with HIV-related lymphomas for the same indications and under the same circumstances that we would use it in patients without HIV infection.”
To arrive at this recommendation, investigators enrolled 43 HIV-infected patients with relapsed or persistent non-Hodgkin lymphoma (NHL) or classical Hodgkin lymphoma (HL) onto the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0803/AIDS Malignancy Consortium (AMC) 071 study.
They reported their findings in Blood.
Eligibility
Patients had to be 15 years or older, have documented evidence of HIV infection, and have a Karnofsky performance status of greater than 70%.
They had to have persistent or recurrent diffuse large B-cell lymphoma, immunoblastic lymphoma, plasmablastic lymphoma, Burkitt lymphoma, Burkitt-like NHL, or classic HL.
Patients could have had no more than 3 prior treatment regimens or 2 or fewer salvage regimens.
They had to have adequate organ function, fewer than 10% blasts in their marrow, no prior autologous or allogeneic transplant, and adequate hematopoietic progenitor cell mobilization of more than 1.5 x 106 CD34+ cells/kg to be eligible.
Transplant regimen
Patients received the BEAM (carmustine, etoposide, cytarabine, and melphalan) transplant regimen on day 0. They did not receive antiretroviral therapy from the time of the start of BEAM until 7 days after completion of the preparative regimen.
Efavirenz was held for 2 weeks prior to BEAM initiation, and an alternative agent was substituted during this time period. Zidovudine was prohibited following transplant because of its myelosuppressive effects.
Patients received growth factor, transfusion, and antimicrobial supportive care according to institutional standards of the transplant center.
Patient characteristics
Of the original 43 patients enrolled, 3 patients experienced disease progression prior to the conditioning regimen and did not undergo transplant. Therefore, investigators did not include them in the study analysis.
Forty patients received ASCT at 16 different transplant centers. They were a median age of 46.9 (range, 22.5–62.2), and 35 were male.
All patients received peripheral blood stem cell grafts at a median dose of 3.9 x 106 CD34+ cells/kg (range, 1.6–11.0). And all patients were able to mobilize hematopoietic progenitor cells in a median of 2 apheresis collections (range, 1–5).
Most patients (n=32; 80%) had a pre-transplant HIV viral load that was undetectable. The median viral load for those 8 patients with detectable disease was 80 copies/mL (range, 50–17,455).
Patients had a median pre-transplant CD4+ T-cell count of 249.0 CD4+/μL (range, 39–797).
Investigators followed the patients for a median of 24.8 months (range, 2.8–27.2).
Response
Seven patients died during the follow-up period, 5 within 1 year of transplant. Four of the deaths within 1 year of transplant were due to relapse or disease progression.
One-year transplant-related mortality (TRM) was 5.2%.
The 1-year overall survival (OS) probability was 87.3%, and, at 2 years, it was 82%. The 2-year progression-free survival (PFS) was 79.8%, and the cumulative incidence of relapse/progression at 2 years was 12.5%.
The probabilities for OS and PFS at 2 years were comparable for both NHL and HL patients.
The median time to post-transplant neutrophil recovery was 11 days, and 97.5% of patients recovered their neutrophil counts by day 28.
The median time to platelet recovery was 18 days, and 92.5% of patients recovered their platelet counts by day 100.
At 100 days post-transplant, 28.9% of the evaluable patients (11/38) had recovered hematologic function. And at 1 year, 74.2% (23/31) had recovered hematologic function.
Adverse events
A little more than half (55%) the patients had at least 1 infectious event within a year of transplant, including 11 who had a severe infection.
Of the 57 infections that occurred post-transplant, 25 were due to bacteria, 22 to viruses, 6 to fungal organisms, 2 to protozoa, and 2 to other organisms. No patient developed Pneumocystis jiroveci pneumonia after transplant.
Nine patients experienced a total of 13 grade 3–5 adverse events. This included infection/sepsis (5 events), venous thromboembolism (2 events), and 1 event each for esophageal candidiasis, enteritis, hyperglycemia, hypernatremia, acute appendicitis, and acute coronary syndrome.
Sixteen patients had to be re-admitted to the hospital after the transplant, for a total of 34 readmissions. Infection (18) and fever (6) were the most common reasons for readmission.
Data comparison
The investigators compared the OS and PFS results to a control group identified through the Center for International Bone Marrow Transplant Research (CIBMTR).
One hundred fifty-one controls matched for age, performance status, primary disease, and disease status at transplant were identified for the 40 HIV-lymphoma cases.
The 1-year OS for the control group was 87.7%, and the 2-year PFS was 69.5%. This compared with the 87.3% and 79.8% for OS and PFS, respectively, for the HIV-lymphoma patients.
These results, the investigators wrote, were not significantly different from outcomes of CIBMTR controls, with a hazard ratio for overall mortality in the HIV-lymphoma patients of 0.67 (95% CI: 0.30–1.50, P=0.33) compared to controls.
And the hazard ratio for treatment failure in the HIV-lymphoma patients was 0.52 (95% CI: 0.2927–1.03, P=0.06) compared to controls.
The investigators concluded that HIV infection alone should not be considered a contraindication to ASCT for patients who otherwise meet transplant inclusion criteria. And ASCT should be considered the standard of care for patients with HIV-related lymphoma, provided that the HIV infection is treatment-responsive.
The team added that these patients should also be considered “appropriate potential participants” for future ASCT clinical trials.
cultured lymphocyte
Image courtesy of CDC
With the advent of effective anti-retroviral therapy, patients with HIV-related lymphoma receive standard therapeutic regimens and achieve outcomes comparable to those of non-HIV-infected individuals.
Based on results of a multicenter phase 2 study, this now extends to treatment with autologous stem cell transplant (ASCT).
Researchers found that outcomes were not significantly different between HIV-infected patients who received ASCT and matched controls.
“These findings are remarkably important for a group of patients who, up until now, have been inconsistently treated,” said lead study author Joseph C. Alvarnas, MD, of City of Hope National Medical Center in Duarte, California.
“Based on our data, autologous stem cell transplant should be considered the standard of care for patients with HIV-related lymphomas for the same indications and under the same circumstances that we would use it in patients without HIV infection.”
To arrive at this recommendation, investigators enrolled 43 HIV-infected patients with relapsed or persistent non-Hodgkin lymphoma (NHL) or classical Hodgkin lymphoma (HL) onto the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0803/AIDS Malignancy Consortium (AMC) 071 study.
They reported their findings in Blood.
Eligibility
Patients had to be 15 years or older, have documented evidence of HIV infection, and have a Karnofsky performance status of greater than 70%.
They had to have persistent or recurrent diffuse large B-cell lymphoma, immunoblastic lymphoma, plasmablastic lymphoma, Burkitt lymphoma, Burkitt-like NHL, or classic HL.
Patients could have had no more than 3 prior treatment regimens or 2 or fewer salvage regimens.
They had to have adequate organ function, fewer than 10% blasts in their marrow, no prior autologous or allogeneic transplant, and adequate hematopoietic progenitor cell mobilization of more than 1.5 x 106 CD34+ cells/kg to be eligible.
Transplant regimen
Patients received the BEAM (carmustine, etoposide, cytarabine, and melphalan) transplant regimen on day 0. They did not receive antiretroviral therapy from the time of the start of BEAM until 7 days after completion of the preparative regimen.
Efavirenz was held for 2 weeks prior to BEAM initiation, and an alternative agent was substituted during this time period. Zidovudine was prohibited following transplant because of its myelosuppressive effects.
Patients received growth factor, transfusion, and antimicrobial supportive care according to institutional standards of the transplant center.
Patient characteristics
Of the original 43 patients enrolled, 3 patients experienced disease progression prior to the conditioning regimen and did not undergo transplant. Therefore, investigators did not include them in the study analysis.
Forty patients received ASCT at 16 different transplant centers. They were a median age of 46.9 (range, 22.5–62.2), and 35 were male.
All patients received peripheral blood stem cell grafts at a median dose of 3.9 x 106 CD34+ cells/kg (range, 1.6–11.0). And all patients were able to mobilize hematopoietic progenitor cells in a median of 2 apheresis collections (range, 1–5).
Most patients (n=32; 80%) had a pre-transplant HIV viral load that was undetectable. The median viral load for those 8 patients with detectable disease was 80 copies/mL (range, 50–17,455).
Patients had a median pre-transplant CD4+ T-cell count of 249.0 CD4+/μL (range, 39–797).
Investigators followed the patients for a median of 24.8 months (range, 2.8–27.2).
Response
Seven patients died during the follow-up period, 5 within 1 year of transplant. Four of the deaths within 1 year of transplant were due to relapse or disease progression.
One-year transplant-related mortality (TRM) was 5.2%.
The 1-year overall survival (OS) probability was 87.3%, and, at 2 years, it was 82%. The 2-year progression-free survival (PFS) was 79.8%, and the cumulative incidence of relapse/progression at 2 years was 12.5%.
The probabilities for OS and PFS at 2 years were comparable for both NHL and HL patients.
The median time to post-transplant neutrophil recovery was 11 days, and 97.5% of patients recovered their neutrophil counts by day 28.
The median time to platelet recovery was 18 days, and 92.5% of patients recovered their platelet counts by day 100.
At 100 days post-transplant, 28.9% of the evaluable patients (11/38) had recovered hematologic function. And at 1 year, 74.2% (23/31) had recovered hematologic function.
Adverse events
A little more than half (55%) the patients had at least 1 infectious event within a year of transplant, including 11 who had a severe infection.
Of the 57 infections that occurred post-transplant, 25 were due to bacteria, 22 to viruses, 6 to fungal organisms, 2 to protozoa, and 2 to other organisms. No patient developed Pneumocystis jiroveci pneumonia after transplant.
Nine patients experienced a total of 13 grade 3–5 adverse events. This included infection/sepsis (5 events), venous thromboembolism (2 events), and 1 event each for esophageal candidiasis, enteritis, hyperglycemia, hypernatremia, acute appendicitis, and acute coronary syndrome.
Sixteen patients had to be re-admitted to the hospital after the transplant, for a total of 34 readmissions. Infection (18) and fever (6) were the most common reasons for readmission.
Data comparison
The investigators compared the OS and PFS results to a control group identified through the Center for International Bone Marrow Transplant Research (CIBMTR).
One hundred fifty-one controls matched for age, performance status, primary disease, and disease status at transplant were identified for the 40 HIV-lymphoma cases.
The 1-year OS for the control group was 87.7%, and the 2-year PFS was 69.5%. This compared with the 87.3% and 79.8% for OS and PFS, respectively, for the HIV-lymphoma patients.
These results, the investigators wrote, were not significantly different from outcomes of CIBMTR controls, with a hazard ratio for overall mortality in the HIV-lymphoma patients of 0.67 (95% CI: 0.30–1.50, P=0.33) compared to controls.
And the hazard ratio for treatment failure in the HIV-lymphoma patients was 0.52 (95% CI: 0.2927–1.03, P=0.06) compared to controls.
The investigators concluded that HIV infection alone should not be considered a contraindication to ASCT for patients who otherwise meet transplant inclusion criteria. And ASCT should be considered the standard of care for patients with HIV-related lymphoma, provided that the HIV infection is treatment-responsive.
The team added that these patients should also be considered “appropriate potential participants” for future ASCT clinical trials.