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Preterm births more common in cancer survivors
Women diagnosed with cancer during their childbearing years have an increased risk of preterm births, according to research published in JAMA Oncology.
The study showed that cancer survivors were more likely than women who never had cancer to give birth prematurely, have underweight babies, and undergo cesarean section deliveries.
The researchers said women diagnosed with cancer during pregnancy may be delivering early in order to start their cancer treatment, but that does not fully explain these findings.
The team also detected an increased risk of preterm delivery in women who had already received cancer treatment.
“We found that women were more likely to deliver preterm if they’ve been treated for cancer overall, with greater risks for women who had chemotherapy,” said study author Hazel B. Nichols, PhD, of University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.
“While we believe these findings are something women should be aware of, we still have a lot of work to do to understand why this risk is becoming apparent and whether or not the children who are born preterm to these women go on to develop any health concerns.”
Dr Nichols and her colleagues analyzed data on 2598 births to female adolescent and young adult cancer survivors (ages 15 to 39) and 12,990 births to women without a cancer diagnosis.
Among cancer survivors, there was a significantly increased prevalence of preterm birth (prevalence ratio [PR]=1.52), low birth weight (PR=1.59), and cesarean delivery (PR=1.08), compared to women without a cancer diagnosis.
Timing of diagnosis and cancer type
When the researchers broke the data down by cancer diagnosis, they found a higher risk of preterm birth and low birth weight for women with lymphoma as well as breast and gynecologic cancers.
The PR for preterm birth was 1.59 for Hodgkin lymphoma, 1.98 for breast cancer, 2.11 for non-Hodgkin lymphoma, and 2.58 for gynecologic cancer. The PR for low birth weight was 1.59 for breast cancer, 2.41 for non-Hodgkin lymphoma, and 2.74 for gynecologic cancer.
The researchers found an increased risk of adverse birth outcomes among women who were diagnosed with cancer while pregnant and before pregnancy.
Among women diagnosed while pregnant, the PR was 2.97 for preterm birth, 2.82 for low birth weight, 1.21 for cesarean delivery, and 1.90 for low Apgar score. Among women diagnosed before pregnancy, the PR was 1.23 for preterm birth and 1.36 for low birth weight.
Role of treatment
Compared to women without a cancer diagnosis, cancer survivors who received chemotherapy but no radiation were more likely to have preterm births (PR=2.11), infants with low birth weight (PR=2.36), and cesarean deliveries (PR=1.16).
There was no significant increase in adverse birth outcomes among cancer survivors who received radiation but not chemotherapy.
Among the cancer survivors, women who received chemotherapy without radiation were more likely to have preterm births (PR=2.12), infants with low birth weight (PR=2.13), and infants who were small for their gestational age (PR=1.43) when compared to women treated with surgery only.
Dr Nichols said the role of treatment is an area of possible future research.
“We’d like to get better information about the types of chemotherapy women receive,” she said. “Chemotherapy is a very broad category, and the agents have very different effects on the body. In the future, we’d like to get more detailed information on the types of drugs that were involved in treatment.” 
Women diagnosed with cancer during their childbearing years have an increased risk of preterm births, according to research published in JAMA Oncology.
The study showed that cancer survivors were more likely than women who never had cancer to give birth prematurely, have underweight babies, and undergo cesarean section deliveries.
The researchers said women diagnosed with cancer during pregnancy may be delivering early in order to start their cancer treatment, but that does not fully explain these findings.
The team also detected an increased risk of preterm delivery in women who had already received cancer treatment.
“We found that women were more likely to deliver preterm if they’ve been treated for cancer overall, with greater risks for women who had chemotherapy,” said study author Hazel B. Nichols, PhD, of University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.
“While we believe these findings are something women should be aware of, we still have a lot of work to do to understand why this risk is becoming apparent and whether or not the children who are born preterm to these women go on to develop any health concerns.”
Dr Nichols and her colleagues analyzed data on 2598 births to female adolescent and young adult cancer survivors (ages 15 to 39) and 12,990 births to women without a cancer diagnosis.
Among cancer survivors, there was a significantly increased prevalence of preterm birth (prevalence ratio [PR]=1.52), low birth weight (PR=1.59), and cesarean delivery (PR=1.08), compared to women without a cancer diagnosis.
Timing of diagnosis and cancer type
When the researchers broke the data down by cancer diagnosis, they found a higher risk of preterm birth and low birth weight for women with lymphoma as well as breast and gynecologic cancers.
The PR for preterm birth was 1.59 for Hodgkin lymphoma, 1.98 for breast cancer, 2.11 for non-Hodgkin lymphoma, and 2.58 for gynecologic cancer. The PR for low birth weight was 1.59 for breast cancer, 2.41 for non-Hodgkin lymphoma, and 2.74 for gynecologic cancer.
The researchers found an increased risk of adverse birth outcomes among women who were diagnosed with cancer while pregnant and before pregnancy.
Among women diagnosed while pregnant, the PR was 2.97 for preterm birth, 2.82 for low birth weight, 1.21 for cesarean delivery, and 1.90 for low Apgar score. Among women diagnosed before pregnancy, the PR was 1.23 for preterm birth and 1.36 for low birth weight.
Role of treatment
Compared to women without a cancer diagnosis, cancer survivors who received chemotherapy but no radiation were more likely to have preterm births (PR=2.11), infants with low birth weight (PR=2.36), and cesarean deliveries (PR=1.16).
There was no significant increase in adverse birth outcomes among cancer survivors who received radiation but not chemotherapy.
Among the cancer survivors, women who received chemotherapy without radiation were more likely to have preterm births (PR=2.12), infants with low birth weight (PR=2.13), and infants who were small for their gestational age (PR=1.43) when compared to women treated with surgery only.
Dr Nichols said the role of treatment is an area of possible future research.
“We’d like to get better information about the types of chemotherapy women receive,” she said. “Chemotherapy is a very broad category, and the agents have very different effects on the body. In the future, we’d like to get more detailed information on the types of drugs that were involved in treatment.”
Women diagnosed with cancer during their childbearing years have an increased risk of preterm births, according to research published in JAMA Oncology.
The study showed that cancer survivors were more likely than women who never had cancer to give birth prematurely, have underweight babies, and undergo cesarean section deliveries.
The researchers said women diagnosed with cancer during pregnancy may be delivering early in order to start their cancer treatment, but that does not fully explain these findings.
The team also detected an increased risk of preterm delivery in women who had already received cancer treatment.
“We found that women were more likely to deliver preterm if they’ve been treated for cancer overall, with greater risks for women who had chemotherapy,” said study author Hazel B. Nichols, PhD, of University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.
“While we believe these findings are something women should be aware of, we still have a lot of work to do to understand why this risk is becoming apparent and whether or not the children who are born preterm to these women go on to develop any health concerns.”
Dr Nichols and her colleagues analyzed data on 2598 births to female adolescent and young adult cancer survivors (ages 15 to 39) and 12,990 births to women without a cancer diagnosis.
Among cancer survivors, there was a significantly increased prevalence of preterm birth (prevalence ratio [PR]=1.52), low birth weight (PR=1.59), and cesarean delivery (PR=1.08), compared to women without a cancer diagnosis.
Timing of diagnosis and cancer type
When the researchers broke the data down by cancer diagnosis, they found a higher risk of preterm birth and low birth weight for women with lymphoma as well as breast and gynecologic cancers.
The PR for preterm birth was 1.59 for Hodgkin lymphoma, 1.98 for breast cancer, 2.11 for non-Hodgkin lymphoma, and 2.58 for gynecologic cancer. The PR for low birth weight was 1.59 for breast cancer, 2.41 for non-Hodgkin lymphoma, and 2.74 for gynecologic cancer.
The researchers found an increased risk of adverse birth outcomes among women who were diagnosed with cancer while pregnant and before pregnancy.
Among women diagnosed while pregnant, the PR was 2.97 for preterm birth, 2.82 for low birth weight, 1.21 for cesarean delivery, and 1.90 for low Apgar score. Among women diagnosed before pregnancy, the PR was 1.23 for preterm birth and 1.36 for low birth weight.
Role of treatment
Compared to women without a cancer diagnosis, cancer survivors who received chemotherapy but no radiation were more likely to have preterm births (PR=2.11), infants with low birth weight (PR=2.36), and cesarean deliveries (PR=1.16).
There was no significant increase in adverse birth outcomes among cancer survivors who received radiation but not chemotherapy.
Among the cancer survivors, women who received chemotherapy without radiation were more likely to have preterm births (PR=2.12), infants with low birth weight (PR=2.13), and infants who were small for their gestational age (PR=1.43) when compared to women treated with surgery only.
Dr Nichols said the role of treatment is an area of possible future research.
“We’d like to get better information about the types of chemotherapy women receive,” she said. “Chemotherapy is a very broad category, and the agents have very different effects on the body. In the future, we’d like to get more detailed information on the types of drugs that were involved in treatment.”
FDA issues update on breast implant-associated ALCL
The US Food and Drug Administration (FDA) has issued an update on breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).
The agency said that, as of February 1, it has received 359 reports of BIA-ALCL.
However, the actual number of BIA-ALCL cases remains difficult to determine due to limitations in reporting and a lack of implant sales data.
The FDA also noted that most of the available data suggest BIA-ALCL occurs more frequently in patients who receive implants with textured surfaces rather than smooth surfaces.
The full FDA update includes background information on BIA-ALCL, a summary of medical device reports (MDRs) and the medical literature, as well as recommendations for patient care.
Background and MDRs
The FDA first identified a possible association between ALCL and breast implants in 2011.
The agency now concurs with the World Health Organization’s designation of BIA-ALCL as a rare T-cell lymphoma occurring in patients with breast implants.
The FDA continues to collect and review information about BIA-ALCL. This includes reviewing MDRs and the medical literature, as well as exchanging information with other international regulators and scientific experts.
The FDA said it has received 359 MDRs of BIA-ALCL, including 9 cases in which the patient died.
Information on the implant surface was available for 239 cases, and 203 of these cases involved textured implants.
Information on the implant filling was available in 312 cases. Of these, 186 patients had implants filled with silicone gel, and 126 had implants filled with saline.
Recommendations
The FDA said healthcare providers performing breast implant surgery should provide patients with the manufacturers’ labeling as well as any other educational materials before surgery and discuss with patients the benefits and risks of the different types of implants.
Providers should consider the possibility of BIA-ALCL when a patient presents with late-onset, persistent peri-implant seroma. The FDA noted that, in some cases, patients presented with capsular contracture or masses adjacent to the breast implant.
Patients with suspected BIA-ALCL should be referred to an appropriate specialist.
When testing for BIA-ALCL, providers should collect fresh seroma fluid and representative portions of the capsule and send these samples for pathology tests.
Diagnostic evaluation of patients with suspected BIA-ALCL should include cytological evaluation of seroma fluid with Wright Giemsa stained smears and cell block immunohistochemistry testing for cluster of differentiation and anaplastic lymphoma kinase markers.
When choosing a treatment approach for patients with BIA-ALCL, providers should consider current clinical practice guidelines, such as those from the National Comprehensive Cancer Network (included in the guidelines for T-cell lymphomas) or the Plastic Surgery Foundation.
Finally, providers should report all confirmed cases of BIA-ALCL to the FDA and to the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma (ALCL) Etiology and Epidemiology (PROFILE Registry).
The US Food and Drug Administration (FDA) has issued an update on breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).
The agency said that, as of February 1, it has received 359 reports of BIA-ALCL.
However, the actual number of BIA-ALCL cases remains difficult to determine due to limitations in reporting and a lack of implant sales data.
The FDA also noted that most of the available data suggest BIA-ALCL occurs more frequently in patients who receive implants with textured surfaces rather than smooth surfaces.
The full FDA update includes background information on BIA-ALCL, a summary of medical device reports (MDRs) and the medical literature, as well as recommendations for patient care.
Background and MDRs
The FDA first identified a possible association between ALCL and breast implants in 2011.
The agency now concurs with the World Health Organization’s designation of BIA-ALCL as a rare T-cell lymphoma occurring in patients with breast implants.
The FDA continues to collect and review information about BIA-ALCL. This includes reviewing MDRs and the medical literature, as well as exchanging information with other international regulators and scientific experts.
The FDA said it has received 359 MDRs of BIA-ALCL, including 9 cases in which the patient died.
Information on the implant surface was available for 239 cases, and 203 of these cases involved textured implants.
Information on the implant filling was available in 312 cases. Of these, 186 patients had implants filled with silicone gel, and 126 had implants filled with saline.
Recommendations
The FDA said healthcare providers performing breast implant surgery should provide patients with the manufacturers’ labeling as well as any other educational materials before surgery and discuss with patients the benefits and risks of the different types of implants.
Providers should consider the possibility of BIA-ALCL when a patient presents with late-onset, persistent peri-implant seroma. The FDA noted that, in some cases, patients presented with capsular contracture or masses adjacent to the breast implant.
Patients with suspected BIA-ALCL should be referred to an appropriate specialist.
When testing for BIA-ALCL, providers should collect fresh seroma fluid and representative portions of the capsule and send these samples for pathology tests.
Diagnostic evaluation of patients with suspected BIA-ALCL should include cytological evaluation of seroma fluid with Wright Giemsa stained smears and cell block immunohistochemistry testing for cluster of differentiation and anaplastic lymphoma kinase markers.
When choosing a treatment approach for patients with BIA-ALCL, providers should consider current clinical practice guidelines, such as those from the National Comprehensive Cancer Network (included in the guidelines for T-cell lymphomas) or the Plastic Surgery Foundation.
Finally, providers should report all confirmed cases of BIA-ALCL to the FDA and to the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma (ALCL) Etiology and Epidemiology (PROFILE Registry).
The US Food and Drug Administration (FDA) has issued an update on breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).
The agency said that, as of February 1, it has received 359 reports of BIA-ALCL.
However, the actual number of BIA-ALCL cases remains difficult to determine due to limitations in reporting and a lack of implant sales data.
The FDA also noted that most of the available data suggest BIA-ALCL occurs more frequently in patients who receive implants with textured surfaces rather than smooth surfaces.
The full FDA update includes background information on BIA-ALCL, a summary of medical device reports (MDRs) and the medical literature, as well as recommendations for patient care.
Background and MDRs
The FDA first identified a possible association between ALCL and breast implants in 2011.
The agency now concurs with the World Health Organization’s designation of BIA-ALCL as a rare T-cell lymphoma occurring in patients with breast implants.
The FDA continues to collect and review information about BIA-ALCL. This includes reviewing MDRs and the medical literature, as well as exchanging information with other international regulators and scientific experts.
The FDA said it has received 359 MDRs of BIA-ALCL, including 9 cases in which the patient died.
Information on the implant surface was available for 239 cases, and 203 of these cases involved textured implants.
Information on the implant filling was available in 312 cases. Of these, 186 patients had implants filled with silicone gel, and 126 had implants filled with saline.
Recommendations
The FDA said healthcare providers performing breast implant surgery should provide patients with the manufacturers’ labeling as well as any other educational materials before surgery and discuss with patients the benefits and risks of the different types of implants.
Providers should consider the possibility of BIA-ALCL when a patient presents with late-onset, persistent peri-implant seroma. The FDA noted that, in some cases, patients presented with capsular contracture or masses adjacent to the breast implant.
Patients with suspected BIA-ALCL should be referred to an appropriate specialist.
When testing for BIA-ALCL, providers should collect fresh seroma fluid and representative portions of the capsule and send these samples for pathology tests.
Diagnostic evaluation of patients with suspected BIA-ALCL should include cytological evaluation of seroma fluid with Wright Giemsa stained smears and cell block immunohistochemistry testing for cluster of differentiation and anaplastic lymphoma kinase markers.
When choosing a treatment approach for patients with BIA-ALCL, providers should consider current clinical practice guidelines, such as those from the National Comprehensive Cancer Network (included in the guidelines for T-cell lymphomas) or the Plastic Surgery Foundation.
Finally, providers should report all confirmed cases of BIA-ALCL to the FDA and to the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma (ALCL) Etiology and Epidemiology (PROFILE Registry).
Therapy can produce durable CRs in NHL
When given after low-dose chemotherapy, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy can produce durable complete responses (CRs) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to research published in the Journal of Clinical Oncology.
In this phase 1 study, the overall response rate was 73%, and 50% of patients had an ongoing CR at last follow-up.
Fifty-five percent of patients experienced grade 3/4 neurologic toxicities, though these events eventually resolved.
This research was conducted under a cooperative research and development agreement between the National Cancer Institute and Kite Pharma, Inc.
Kite is developing the CAR T-cell therapy axicabtagene ciloleucel (formerly known as KTE-C19), and the therapy tested in this trial has the same CAR construct as axicabtagene ciloleucel.
Results from this study (NCT00924326) were previously published in the Journal of Clinical Oncology in 2014.
The current report included 22 patients with relapsed/refractory NHL. Seventeen patients had diffuse large B-cell lymphoma (DLBCL), 2 had primary mediastinal B-cell lymphoma (PMBCL), 2 had follicular lymphoma (FL), and 1 had mantle cell lymphoma (MCL).
Patients received a single dose of CAR T cells 2 days after a low-dose chemotherapy conditioning regimen consisting of cyclophosphamide and fludarabine.
Response
The overall response rate was 73% (16/22), with a CR rate of 55% (n=12) and a partial response (PR) rate of 18% (n=4).
Among patients with DLBCL, there were 9 CRs, 4 PRs, 1 patient with stable disease, and 3 patients with progressive disease.
Both FL patients achieved a CR, as did the patient with MCL. One patient with PMBCL had stable disease, and the other progressed.
Eleven of the 12 CRs are ongoing, with durations ranging from more than 7 months to more than 24 months. The median duration of CR is 12.5 months.
The researchers found that serum IL-15 levels and CAR T-cell expansion correlated with treatment response (CR or PR).
The median peak blood CAR+ cell level was 98/μL in patients who achieved a response and 15/μL in those who did not (P=0.027).
High serum IL-15 levels were significantly associated with high peak blood CAR+ cell levels (P=0.001) and response (P<0.001).
Toxicity
Fifty-five percent of patients had grade 3 or 4 neurologic toxicities, the most common of which were dysphasia (n=9) and confusion (n=8).
The researchers said all acute toxicities resolved completely, and none of the patients died as a result of toxicity.
One patient experienced vision loss 3 months after receiving CAR T-cell therapy. The researchers said they could not confirm the cause of the vision loss, but it is consistent with fludarabine toxicity.
One patient developed myelodysplastic syndrome, which was thought to be related to prior therapy.
The researchers noted that patients who experienced grade 3/4 neurologic toxicity had significantly higher levels of blood CAR+ cells than patients who had neurologic toxicities of a lower grade (P=0.003).
In addition, peak levels of serum IL-10 and IL-15 were higher in patients with grade 3/4 neurologic toxicities (P=0.006 and 0.014, respectively).
When given after low-dose chemotherapy, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy can produce durable complete responses (CRs) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to research published in the Journal of Clinical Oncology.
In this phase 1 study, the overall response rate was 73%, and 50% of patients had an ongoing CR at last follow-up.
Fifty-five percent of patients experienced grade 3/4 neurologic toxicities, though these events eventually resolved.
This research was conducted under a cooperative research and development agreement between the National Cancer Institute and Kite Pharma, Inc.
Kite is developing the CAR T-cell therapy axicabtagene ciloleucel (formerly known as KTE-C19), and the therapy tested in this trial has the same CAR construct as axicabtagene ciloleucel.
Results from this study (NCT00924326) were previously published in the Journal of Clinical Oncology in 2014.
The current report included 22 patients with relapsed/refractory NHL. Seventeen patients had diffuse large B-cell lymphoma (DLBCL), 2 had primary mediastinal B-cell lymphoma (PMBCL), 2 had follicular lymphoma (FL), and 1 had mantle cell lymphoma (MCL).
Patients received a single dose of CAR T cells 2 days after a low-dose chemotherapy conditioning regimen consisting of cyclophosphamide and fludarabine.
Response
The overall response rate was 73% (16/22), with a CR rate of 55% (n=12) and a partial response (PR) rate of 18% (n=4).
Among patients with DLBCL, there were 9 CRs, 4 PRs, 1 patient with stable disease, and 3 patients with progressive disease.
Both FL patients achieved a CR, as did the patient with MCL. One patient with PMBCL had stable disease, and the other progressed.
Eleven of the 12 CRs are ongoing, with durations ranging from more than 7 months to more than 24 months. The median duration of CR is 12.5 months.
The researchers found that serum IL-15 levels and CAR T-cell expansion correlated with treatment response (CR or PR).
The median peak blood CAR+ cell level was 98/μL in patients who achieved a response and 15/μL in those who did not (P=0.027).
High serum IL-15 levels were significantly associated with high peak blood CAR+ cell levels (P=0.001) and response (P<0.001).
Toxicity
Fifty-five percent of patients had grade 3 or 4 neurologic toxicities, the most common of which were dysphasia (n=9) and confusion (n=8).
The researchers said all acute toxicities resolved completely, and none of the patients died as a result of toxicity.
One patient experienced vision loss 3 months after receiving CAR T-cell therapy. The researchers said they could not confirm the cause of the vision loss, but it is consistent with fludarabine toxicity.
One patient developed myelodysplastic syndrome, which was thought to be related to prior therapy.
The researchers noted that patients who experienced grade 3/4 neurologic toxicity had significantly higher levels of blood CAR+ cells than patients who had neurologic toxicities of a lower grade (P=0.003).
In addition, peak levels of serum IL-10 and IL-15 were higher in patients with grade 3/4 neurologic toxicities (P=0.006 and 0.014, respectively).
When given after low-dose chemotherapy, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy can produce durable complete responses (CRs) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to research published in the Journal of Clinical Oncology.
In this phase 1 study, the overall response rate was 73%, and 50% of patients had an ongoing CR at last follow-up.
Fifty-five percent of patients experienced grade 3/4 neurologic toxicities, though these events eventually resolved.
This research was conducted under a cooperative research and development agreement between the National Cancer Institute and Kite Pharma, Inc.
Kite is developing the CAR T-cell therapy axicabtagene ciloleucel (formerly known as KTE-C19), and the therapy tested in this trial has the same CAR construct as axicabtagene ciloleucel.
Results from this study (NCT00924326) were previously published in the Journal of Clinical Oncology in 2014.
The current report included 22 patients with relapsed/refractory NHL. Seventeen patients had diffuse large B-cell lymphoma (DLBCL), 2 had primary mediastinal B-cell lymphoma (PMBCL), 2 had follicular lymphoma (FL), and 1 had mantle cell lymphoma (MCL).
Patients received a single dose of CAR T cells 2 days after a low-dose chemotherapy conditioning regimen consisting of cyclophosphamide and fludarabine.
Response
The overall response rate was 73% (16/22), with a CR rate of 55% (n=12) and a partial response (PR) rate of 18% (n=4).
Among patients with DLBCL, there were 9 CRs, 4 PRs, 1 patient with stable disease, and 3 patients with progressive disease.
Both FL patients achieved a CR, as did the patient with MCL. One patient with PMBCL had stable disease, and the other progressed.
Eleven of the 12 CRs are ongoing, with durations ranging from more than 7 months to more than 24 months. The median duration of CR is 12.5 months.
The researchers found that serum IL-15 levels and CAR T-cell expansion correlated with treatment response (CR or PR).
The median peak blood CAR+ cell level was 98/μL in patients who achieved a response and 15/μL in those who did not (P=0.027).
High serum IL-15 levels were significantly associated with high peak blood CAR+ cell levels (P=0.001) and response (P<0.001).
Toxicity
Fifty-five percent of patients had grade 3 or 4 neurologic toxicities, the most common of which were dysphasia (n=9) and confusion (n=8).
The researchers said all acute toxicities resolved completely, and none of the patients died as a result of toxicity.
One patient experienced vision loss 3 months after receiving CAR T-cell therapy. The researchers said they could not confirm the cause of the vision loss, but it is consistent with fludarabine toxicity.
One patient developed myelodysplastic syndrome, which was thought to be related to prior therapy.
The researchers noted that patients who experienced grade 3/4 neurologic toxicity had significantly higher levels of blood CAR+ cells than patients who had neurologic toxicities of a lower grade (P=0.003).
In addition, peak levels of serum IL-10 and IL-15 were higher in patients with grade 3/4 neurologic toxicities (P=0.006 and 0.014, respectively).
Veterans don’t have higher risk of leukemia, lymphoma
People who have served in the Armed Forces do not have an increased risk of leukemia or lymphoma, according to research published in Cancer Epidemiology.
Researchers analyzed the long-term risks of developing leukemia, Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL) in veterans living in Scotland.
At a mean 30 years of follow-up, there were no significant differences in the risk of the aforementioned malignancies between veterans and non-veterans in Scotland.
This retrospective study included 56,205 veterans and 172,741 non-veterans.
The veterans’ earliest date of entering service was January 1960, and the latest date of leaving service was December 2012.
At a mean follow-up of 29.3 years, 294 (0.52%) veterans and 974 (0.56%) non-veterans were diagnosed with leukemia, HL, or NHL.
There were 125 (0.22%) cases of leukemia in veterans and 365 (0.21%) in non-veterans. There were 59 (0.10%) cases of HL in veterans and 182 (0.11%) in non-veterans. And there were 144 (0.26%) cases of NHL in veterans and 538 (0.31%) in non-veterans.
There was no significant difference in the risk of all 3 cancer types between the veterans and non-veterans. The unadjusted hazard ratio (HR) was 0.96 (P=0.541).
There were no significant differences in an adjusted analysis either. (The analysis was adjusted for regional deprivation, which takes into account information on income, employment, health, education, housing, crime, and access to services.)
The adjusted HR was 1.03 (P=0.773) for leukemias, 1.19 (P=0.272) for HL, and 0.86 (P=0.110) for NHL.
“This is an important study which provides reassurance that military service in the last 50 years does not increase people’s risk of leukemia overall,” said study author Beverly Bergman, PhD, of the University of Glasgow in the UK.
“The Armed Forces comply with all relevant health and safety legislation and regulations, and we can now see that their risk is no different from the general population.”
People who have served in the Armed Forces do not have an increased risk of leukemia or lymphoma, according to research published in Cancer Epidemiology.
Researchers analyzed the long-term risks of developing leukemia, Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL) in veterans living in Scotland.
At a mean 30 years of follow-up, there were no significant differences in the risk of the aforementioned malignancies between veterans and non-veterans in Scotland.
This retrospective study included 56,205 veterans and 172,741 non-veterans.
The veterans’ earliest date of entering service was January 1960, and the latest date of leaving service was December 2012.
At a mean follow-up of 29.3 years, 294 (0.52%) veterans and 974 (0.56%) non-veterans were diagnosed with leukemia, HL, or NHL.
There were 125 (0.22%) cases of leukemia in veterans and 365 (0.21%) in non-veterans. There were 59 (0.10%) cases of HL in veterans and 182 (0.11%) in non-veterans. And there were 144 (0.26%) cases of NHL in veterans and 538 (0.31%) in non-veterans.
There was no significant difference in the risk of all 3 cancer types between the veterans and non-veterans. The unadjusted hazard ratio (HR) was 0.96 (P=0.541).
There were no significant differences in an adjusted analysis either. (The analysis was adjusted for regional deprivation, which takes into account information on income, employment, health, education, housing, crime, and access to services.)
The adjusted HR was 1.03 (P=0.773) for leukemias, 1.19 (P=0.272) for HL, and 0.86 (P=0.110) for NHL.
“This is an important study which provides reassurance that military service in the last 50 years does not increase people’s risk of leukemia overall,” said study author Beverly Bergman, PhD, of the University of Glasgow in the UK.
“The Armed Forces comply with all relevant health and safety legislation and regulations, and we can now see that their risk is no different from the general population.”
People who have served in the Armed Forces do not have an increased risk of leukemia or lymphoma, according to research published in Cancer Epidemiology.
Researchers analyzed the long-term risks of developing leukemia, Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL) in veterans living in Scotland.
At a mean 30 years of follow-up, there were no significant differences in the risk of the aforementioned malignancies between veterans and non-veterans in Scotland.
This retrospective study included 56,205 veterans and 172,741 non-veterans.
The veterans’ earliest date of entering service was January 1960, and the latest date of leaving service was December 2012.
At a mean follow-up of 29.3 years, 294 (0.52%) veterans and 974 (0.56%) non-veterans were diagnosed with leukemia, HL, or NHL.
There were 125 (0.22%) cases of leukemia in veterans and 365 (0.21%) in non-veterans. There were 59 (0.10%) cases of HL in veterans and 182 (0.11%) in non-veterans. And there were 144 (0.26%) cases of NHL in veterans and 538 (0.31%) in non-veterans.
There was no significant difference in the risk of all 3 cancer types between the veterans and non-veterans. The unadjusted hazard ratio (HR) was 0.96 (P=0.541).
There were no significant differences in an adjusted analysis either. (The analysis was adjusted for regional deprivation, which takes into account information on income, employment, health, education, housing, crime, and access to services.)
The adjusted HR was 1.03 (P=0.773) for leukemias, 1.19 (P=0.272) for HL, and 0.86 (P=0.110) for NHL.
“This is an important study which provides reassurance that military service in the last 50 years does not increase people’s risk of leukemia overall,” said study author Beverly Bergman, PhD, of the University of Glasgow in the UK.
“The Armed Forces comply with all relevant health and safety legislation and regulations, and we can now see that their risk is no different from the general population.”
Selinexor trials placed on partial hold
The US Food and Drug Administration (FDA) has placed a partial clinical hold on all trials of selinexor (KPT-330).
Selinexor is an inhibitor being evaluated in multiple trials of patients with relapsed and/or refractory hematologic and solid tumor malignancies.
While the partial clinical hold remains in effect, patients with stable disease or better may remain on selinexor.
However, no new patients may be enrolled in selinexor trials until the hold is lifted.
The FDA has indicated that the partial clinical hold is due to incomplete information in the existing version of the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.
Karyopharm Therapeutics Inc., the company developing selinexor, said it has amended the brochure, updated the informed consent documents accordingly, and submitted the documents to the FDA as requested.
As of March 10, Karyopharm had provided all requested materials to the FDA believed to be required to lift the partial clinical hold. By regulation, the FDA has 30 days from the receipt of Karyopharm’s submission to notify the company whether the partial clinical hold is lifted.
Karyopharm said it is working with the FDA to seek the release of the hold and resume enrollment in its selinexor trials as expeditiously as possible. The company believes its previously disclosed enrollment rates and timelines for its ongoing trials will remain materially unchanged.
About selinexor
Selinexor is a selective inhibitor of nuclear export (SINE) XPO1 antagonist. The drug binds with and inhibits XPO1, leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to induce apoptosis in cancer cells while largely sparing normal cells.
To date, more than 1900 patients have been treated with selinexor. The drug is currently being evaluated in several trials across multiple cancer indications.
One of these is the phase 2 SOPRA trial, in which selinexor is being compared to investigator’s choice of therapy (1 of 3 potential salvage therapies). The trial is enrolling patients 60 years of age or older with relapsed or refractory acute myeloid leukemia who are ineligible for standard intensive chemotherapy and/or transplant.
The SADAL study is a phase 2b trial comparing high and low doses of selinexor in patients with relapsed and/or refractory de novo diffuse large B-cell lymphoma who have no therapeutic options of demonstrated clinical benefit.
STORM is a phase 2b trial evaluating selinexor and low-dose dexamethasone in patients with heavily pretreated multiple myeloma (MM). And STOMP is a phase 1b/2 study evaluating selinexor in combination with existing therapies across the broader population in MM.
Karyopharm is also planning a randomized, phase 3 study known as BOSTON. In this trial, researchers will compare selinexor plus bortezomib and low-dose dexamethasone to bortezomib and low-dose dexamethasone in MM patients who have had 1 to 3 prior lines of therapy.
Additional phase 1, 2, and 3 studies are ongoing or currently planned.
The US Food and Drug Administration (FDA) has placed a partial clinical hold on all trials of selinexor (KPT-330).
Selinexor is an inhibitor being evaluated in multiple trials of patients with relapsed and/or refractory hematologic and solid tumor malignancies.
While the partial clinical hold remains in effect, patients with stable disease or better may remain on selinexor.
However, no new patients may be enrolled in selinexor trials until the hold is lifted.
The FDA has indicated that the partial clinical hold is due to incomplete information in the existing version of the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.
Karyopharm Therapeutics Inc., the company developing selinexor, said it has amended the brochure, updated the informed consent documents accordingly, and submitted the documents to the FDA as requested.
As of March 10, Karyopharm had provided all requested materials to the FDA believed to be required to lift the partial clinical hold. By regulation, the FDA has 30 days from the receipt of Karyopharm’s submission to notify the company whether the partial clinical hold is lifted.
Karyopharm said it is working with the FDA to seek the release of the hold and resume enrollment in its selinexor trials as expeditiously as possible. The company believes its previously disclosed enrollment rates and timelines for its ongoing trials will remain materially unchanged.
About selinexor
Selinexor is a selective inhibitor of nuclear export (SINE) XPO1 antagonist. The drug binds with and inhibits XPO1, leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to induce apoptosis in cancer cells while largely sparing normal cells.
To date, more than 1900 patients have been treated with selinexor. The drug is currently being evaluated in several trials across multiple cancer indications.
One of these is the phase 2 SOPRA trial, in which selinexor is being compared to investigator’s choice of therapy (1 of 3 potential salvage therapies). The trial is enrolling patients 60 years of age or older with relapsed or refractory acute myeloid leukemia who are ineligible for standard intensive chemotherapy and/or transplant.
The SADAL study is a phase 2b trial comparing high and low doses of selinexor in patients with relapsed and/or refractory de novo diffuse large B-cell lymphoma who have no therapeutic options of demonstrated clinical benefit.
STORM is a phase 2b trial evaluating selinexor and low-dose dexamethasone in patients with heavily pretreated multiple myeloma (MM). And STOMP is a phase 1b/2 study evaluating selinexor in combination with existing therapies across the broader population in MM.
Karyopharm is also planning a randomized, phase 3 study known as BOSTON. In this trial, researchers will compare selinexor plus bortezomib and low-dose dexamethasone to bortezomib and low-dose dexamethasone in MM patients who have had 1 to 3 prior lines of therapy.
Additional phase 1, 2, and 3 studies are ongoing or currently planned.
The US Food and Drug Administration (FDA) has placed a partial clinical hold on all trials of selinexor (KPT-330).
Selinexor is an inhibitor being evaluated in multiple trials of patients with relapsed and/or refractory hematologic and solid tumor malignancies.
While the partial clinical hold remains in effect, patients with stable disease or better may remain on selinexor.
However, no new patients may be enrolled in selinexor trials until the hold is lifted.
The FDA has indicated that the partial clinical hold is due to incomplete information in the existing version of the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.
Karyopharm Therapeutics Inc., the company developing selinexor, said it has amended the brochure, updated the informed consent documents accordingly, and submitted the documents to the FDA as requested.
As of March 10, Karyopharm had provided all requested materials to the FDA believed to be required to lift the partial clinical hold. By regulation, the FDA has 30 days from the receipt of Karyopharm’s submission to notify the company whether the partial clinical hold is lifted.
Karyopharm said it is working with the FDA to seek the release of the hold and resume enrollment in its selinexor trials as expeditiously as possible. The company believes its previously disclosed enrollment rates and timelines for its ongoing trials will remain materially unchanged.
About selinexor
Selinexor is a selective inhibitor of nuclear export (SINE) XPO1 antagonist. The drug binds with and inhibits XPO1, leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to induce apoptosis in cancer cells while largely sparing normal cells.
To date, more than 1900 patients have been treated with selinexor. The drug is currently being evaluated in several trials across multiple cancer indications.
One of these is the phase 2 SOPRA trial, in which selinexor is being compared to investigator’s choice of therapy (1 of 3 potential salvage therapies). The trial is enrolling patients 60 years of age or older with relapsed or refractory acute myeloid leukemia who are ineligible for standard intensive chemotherapy and/or transplant.
The SADAL study is a phase 2b trial comparing high and low doses of selinexor in patients with relapsed and/or refractory de novo diffuse large B-cell lymphoma who have no therapeutic options of demonstrated clinical benefit.
STORM is a phase 2b trial evaluating selinexor and low-dose dexamethasone in patients with heavily pretreated multiple myeloma (MM). And STOMP is a phase 1b/2 study evaluating selinexor in combination with existing therapies across the broader population in MM.
Karyopharm is also planning a randomized, phase 3 study known as BOSTON. In this trial, researchers will compare selinexor plus bortezomib and low-dose dexamethasone to bortezomib and low-dose dexamethasone in MM patients who have had 1 to 3 prior lines of therapy.
Additional phase 1, 2, and 3 studies are ongoing or currently planned.
Drug receives orphan designation for DLBCL
The US Food and Drug Administration (FDA) has granted orphan drug designation for eFT508 to treat diffuse large B-cell lymphoma (DLBCL).
eFT508 is a highly selective inhibitor of MNK1 and MNK2, enzymes that integrate signals from several oncogenic and immune signaling pathways.
The FDA grants orphan designation to drugs or biologics intended to treat a disease or condition affecting fewer than 200,000 patients in the US.
The orphan designation for eFT508 provides several incentives for eFFECTOR Therapeutics, the company developing eFT508.
These incentives include increased access to FDA reviewers to discuss clinical trial designs, the ability to qualify for tax credits for certain clinical research costs, the ability to apply for annual grant funding, a waiver of Prescription Drug User Fee Act filing fees, and the potential for 7 years of US marketing exclusivity if eFT508 is approved.
eFFECTOR has dosed the first subject in a phase 1/2 trial of eFT508 in patients with B-cell hematologic malignancies. The study is designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of eFT508.
eFFECTOR presented preclinical research of eFT508 in DLBCL at the 2015 ASH Annual Meeting. The poster is available for download from the eFFECTOR website.
The researchers reported that eFT508 demonstrated anti-proliferative activity against multiple DLBCL cell lines, including the TMD8, OCI-Ly3, and HBL1 cell lines.
eFT508 also exhibited “significant anti-tumor activity” in mouse models of TMD8 and HBL-1 ABC-DLBCL.
Finally, the researchers found that eFT508 synergized with everolimus, ibrutinib, and venetoclax both in vitro and in vivo. 
The US Food and Drug Administration (FDA) has granted orphan drug designation for eFT508 to treat diffuse large B-cell lymphoma (DLBCL).
eFT508 is a highly selective inhibitor of MNK1 and MNK2, enzymes that integrate signals from several oncogenic and immune signaling pathways.
The FDA grants orphan designation to drugs or biologics intended to treat a disease or condition affecting fewer than 200,000 patients in the US.
The orphan designation for eFT508 provides several incentives for eFFECTOR Therapeutics, the company developing eFT508.
These incentives include increased access to FDA reviewers to discuss clinical trial designs, the ability to qualify for tax credits for certain clinical research costs, the ability to apply for annual grant funding, a waiver of Prescription Drug User Fee Act filing fees, and the potential for 7 years of US marketing exclusivity if eFT508 is approved.
eFFECTOR has dosed the first subject in a phase 1/2 trial of eFT508 in patients with B-cell hematologic malignancies. The study is designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of eFT508.
eFFECTOR presented preclinical research of eFT508 in DLBCL at the 2015 ASH Annual Meeting. The poster is available for download from the eFFECTOR website.
The researchers reported that eFT508 demonstrated anti-proliferative activity against multiple DLBCL cell lines, including the TMD8, OCI-Ly3, and HBL1 cell lines.
eFT508 also exhibited “significant anti-tumor activity” in mouse models of TMD8 and HBL-1 ABC-DLBCL.
Finally, the researchers found that eFT508 synergized with everolimus, ibrutinib, and venetoclax both in vitro and in vivo.
The US Food and Drug Administration (FDA) has granted orphan drug designation for eFT508 to treat diffuse large B-cell lymphoma (DLBCL).
eFT508 is a highly selective inhibitor of MNK1 and MNK2, enzymes that integrate signals from several oncogenic and immune signaling pathways.
The FDA grants orphan designation to drugs or biologics intended to treat a disease or condition affecting fewer than 200,000 patients in the US.
The orphan designation for eFT508 provides several incentives for eFFECTOR Therapeutics, the company developing eFT508.
These incentives include increased access to FDA reviewers to discuss clinical trial designs, the ability to qualify for tax credits for certain clinical research costs, the ability to apply for annual grant funding, a waiver of Prescription Drug User Fee Act filing fees, and the potential for 7 years of US marketing exclusivity if eFT508 is approved.
eFFECTOR has dosed the first subject in a phase 1/2 trial of eFT508 in patients with B-cell hematologic malignancies. The study is designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of eFT508.
eFFECTOR presented preclinical research of eFT508 in DLBCL at the 2015 ASH Annual Meeting. The poster is available for download from the eFFECTOR website.
The researchers reported that eFT508 demonstrated anti-proliferative activity against multiple DLBCL cell lines, including the TMD8, OCI-Ly3, and HBL1 cell lines.
eFT508 also exhibited “significant anti-tumor activity” in mouse models of TMD8 and HBL-1 ABC-DLBCL.
Finally, the researchers found that eFT508 synergized with everolimus, ibrutinib, and venetoclax both in vitro and in vivo.
Cell-free DNA mutational analysis in AITL
SAN FRANCISCO—An exploratory study suggests cell-free DNA from peripheral blood may be a viable alternative to tumor DNA for mutational profiling in angioimmunoblastic T-cell lymphoma (AITL).
Investigators sequenced cell-free DNA and tumor DNA collected from 13 patients with AITL and found that, in 85% of cases, there was concordance between the tumor mutational profile and the cell-free DNA mutational profile.
“The cell-free DNA mutational analysis seems to mirror the mutational analysis of the tumor in the majority of cases,” said Neha Mehta-Shah, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
“This may be particularly interesting when we don’t have very much tumor DNA available for sequencing, as occurs frequently in this patient population.”
Dr Mehta-Shah presented these findings at the 9th Annual T-cell Lymphoma Forum.
She said the primary objective of this study was to evaluate whether somatic mutation analysis of cell-free DNA for IDH2 correlates with tumor mutational profiling for IDH2.
The secondary objective was to evaluate whether somatic mutational analysis of cell-free DNA mirrors the mutational profile of the tumor.
So Dr Mehta-Shah and her colleagues sequenced various samples from 14 patients with AITL (4 who were newly diagnosed and 10 with relapsed disease).
The investigators compared cell-free DNA obtained from peripheral blood samples with genomic DNA obtained from primary tumor biopsies and with DNA from peripheral blood mononuclear cells (for germline comparison). One of the 14 patients didn’t have tumor tissue available, so 13 patients were included in the analysis.
The team performed targeted next-generation sequencing using Memorial Sloan Kettering Cancer Center’s IMPACT platform, which sequences 410 genes known to be recurrently mutated in cancer.
The investigators observed concordance between the tumor mutational profile and the cell-free DNA profile in 85% of cases (11/13).
Identical alterations in TET2, RHOA, IDH2, DNMT3A, and ROS1 were detected in cell-free DNA from peripheral blood and tumor genomic DNA, with a similar variant allele frequency.
On the other hand, mutational analysis of cell-free DNA obtained from urine samples from 2 of the patients did not correlate with somatic mutations from tumor DNA.
This research also revealed that some samples had multiple mutations in TET2, which are indicative of subclonal populations.
And sequential samples from 2 patients, collected at the start of salvage therapy and at subsequent relapse, showed the disappearance of mutations in RHOA, TET2, and IDH2. This observation has been attributed to clonal evolution and/or changes in overall disease burden.
SAN FRANCISCO—An exploratory study suggests cell-free DNA from peripheral blood may be a viable alternative to tumor DNA for mutational profiling in angioimmunoblastic T-cell lymphoma (AITL).
Investigators sequenced cell-free DNA and tumor DNA collected from 13 patients with AITL and found that, in 85% of cases, there was concordance between the tumor mutational profile and the cell-free DNA mutational profile.
“The cell-free DNA mutational analysis seems to mirror the mutational analysis of the tumor in the majority of cases,” said Neha Mehta-Shah, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
“This may be particularly interesting when we don’t have very much tumor DNA available for sequencing, as occurs frequently in this patient population.”
Dr Mehta-Shah presented these findings at the 9th Annual T-cell Lymphoma Forum.
She said the primary objective of this study was to evaluate whether somatic mutation analysis of cell-free DNA for IDH2 correlates with tumor mutational profiling for IDH2.
The secondary objective was to evaluate whether somatic mutational analysis of cell-free DNA mirrors the mutational profile of the tumor.
So Dr Mehta-Shah and her colleagues sequenced various samples from 14 patients with AITL (4 who were newly diagnosed and 10 with relapsed disease).
The investigators compared cell-free DNA obtained from peripheral blood samples with genomic DNA obtained from primary tumor biopsies and with DNA from peripheral blood mononuclear cells (for germline comparison). One of the 14 patients didn’t have tumor tissue available, so 13 patients were included in the analysis.
The team performed targeted next-generation sequencing using Memorial Sloan Kettering Cancer Center’s IMPACT platform, which sequences 410 genes known to be recurrently mutated in cancer.
The investigators observed concordance between the tumor mutational profile and the cell-free DNA profile in 85% of cases (11/13).
Identical alterations in TET2, RHOA, IDH2, DNMT3A, and ROS1 were detected in cell-free DNA from peripheral blood and tumor genomic DNA, with a similar variant allele frequency.
On the other hand, mutational analysis of cell-free DNA obtained from urine samples from 2 of the patients did not correlate with somatic mutations from tumor DNA.
This research also revealed that some samples had multiple mutations in TET2, which are indicative of subclonal populations.
And sequential samples from 2 patients, collected at the start of salvage therapy and at subsequent relapse, showed the disappearance of mutations in RHOA, TET2, and IDH2. This observation has been attributed to clonal evolution and/or changes in overall disease burden.
SAN FRANCISCO—An exploratory study suggests cell-free DNA from peripheral blood may be a viable alternative to tumor DNA for mutational profiling in angioimmunoblastic T-cell lymphoma (AITL).
Investigators sequenced cell-free DNA and tumor DNA collected from 13 patients with AITL and found that, in 85% of cases, there was concordance between the tumor mutational profile and the cell-free DNA mutational profile.
“The cell-free DNA mutational analysis seems to mirror the mutational analysis of the tumor in the majority of cases,” said Neha Mehta-Shah, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
“This may be particularly interesting when we don’t have very much tumor DNA available for sequencing, as occurs frequently in this patient population.”
Dr Mehta-Shah presented these findings at the 9th Annual T-cell Lymphoma Forum.
She said the primary objective of this study was to evaluate whether somatic mutation analysis of cell-free DNA for IDH2 correlates with tumor mutational profiling for IDH2.
The secondary objective was to evaluate whether somatic mutational analysis of cell-free DNA mirrors the mutational profile of the tumor.
So Dr Mehta-Shah and her colleagues sequenced various samples from 14 patients with AITL (4 who were newly diagnosed and 10 with relapsed disease).
The investigators compared cell-free DNA obtained from peripheral blood samples with genomic DNA obtained from primary tumor biopsies and with DNA from peripheral blood mononuclear cells (for germline comparison). One of the 14 patients didn’t have tumor tissue available, so 13 patients were included in the analysis.
The team performed targeted next-generation sequencing using Memorial Sloan Kettering Cancer Center’s IMPACT platform, which sequences 410 genes known to be recurrently mutated in cancer.
The investigators observed concordance between the tumor mutational profile and the cell-free DNA profile in 85% of cases (11/13).
Identical alterations in TET2, RHOA, IDH2, DNMT3A, and ROS1 were detected in cell-free DNA from peripheral blood and tumor genomic DNA, with a similar variant allele frequency.
On the other hand, mutational analysis of cell-free DNA obtained from urine samples from 2 of the patients did not correlate with somatic mutations from tumor DNA.
This research also revealed that some samples had multiple mutations in TET2, which are indicative of subclonal populations.
And sequential samples from 2 patients, collected at the start of salvage therapy and at subsequent relapse, showed the disappearance of mutations in RHOA, TET2, and IDH2. This observation has been attributed to clonal evolution and/or changes in overall disease burden.
Chlormethine gel approved to treat mycosis fungoides
The European Commission has granted marketing authorization for chlormethine gel (Ledaga®) as a treatment for adults with mycosis fungoides (MF), but the product is not expected to be available until next year.
Ledaga is a hybrid medicine of Caryolysine, which has been approved for use in the European Union since 1946.
Hybrid medicines have a different strength, are administered differently, or have a different indication from the reference medicine.
Ledaga contains the same active substance as Caryolysine—chlormethine, a bifunctional alkylating agent that inhibits rapidly proliferating cells—but Ledaga is a gel intended for cutaneous use.
Actelion Pharmaceuticals Ltd, the company developing Ledaga, has agreed to fulfill a list of post-approval measures for the product proposed by the European Medicines Agency’s Committee for Medicinal Products for Human Use.
Subject to fulfilling the agreed commitments and achieving market access in various countries, a potential first European launch of Ledaga is not expected before January 2018. When it is launched, Ledaga will be available as a 160 μg/g gel.
Phase 2 study
The authorization of hybrid medicines depends partly on the results of tests on the reference medicine and partly on new data from clinical trials.
The marketing authorization for Ledaga is based, in part, on results of a multicenter, randomized, observer-blinded, active-controlled study of patients with stage I and IIA MF. Results from this phase 2 study were published in JAMA Dermatology.
The study enrolled 260 MF patients who were randomized 1:1 to receive topical treatment with 0.02% chlormethine gel (Ledaga) or compounded control—0.02% chlormethine compounded in Aquaphor® ointment—once daily for up to 12 months.
A response was defined as at least a 50% improvement in the baseline Composite Assessment of Index Lesion Severity score.
In the intent-to-treat population, 59% (76/130) of patients who received Ledaga achieved a clinical response, compared to 48% (62/130) of patients treated with the compounded control. The rate of complete response was 14% (n=18) and 12% (n=15), respectively.
Patients who were treated for at least 6 months were included in the efficacy-evaluable population. In this population, 77% (69/90) of patients who received Ledaga achieved a clinical response, compared to 59% (56/95) of patients treated with the compounded control. The rate of complete response was 19% (n=17) and 15% (n=14), respectively.
Reductions in mean lesion severity were seen as early as 4 weeks into the study, with further reductions observed with continuing therapy. The time to first confirmed response favored Ledaga.
The most frequent adverse reactions reported with Ledaga were skin-related—dermatitis (55%; eg, skin irritation, erythema, rash, urticaria, skin-burning sensation, skin pain), pruritus (20%), skin infections (12%), skin ulceration and blistering (6%), and skin hyperpigmentation (6%).
No systemic absorption of chlormethine was detected with treatment.
The European Commission has granted marketing authorization for chlormethine gel (Ledaga®) as a treatment for adults with mycosis fungoides (MF), but the product is not expected to be available until next year.
Ledaga is a hybrid medicine of Caryolysine, which has been approved for use in the European Union since 1946.
Hybrid medicines have a different strength, are administered differently, or have a different indication from the reference medicine.
Ledaga contains the same active substance as Caryolysine—chlormethine, a bifunctional alkylating agent that inhibits rapidly proliferating cells—but Ledaga is a gel intended for cutaneous use.
Actelion Pharmaceuticals Ltd, the company developing Ledaga, has agreed to fulfill a list of post-approval measures for the product proposed by the European Medicines Agency’s Committee for Medicinal Products for Human Use.
Subject to fulfilling the agreed commitments and achieving market access in various countries, a potential first European launch of Ledaga is not expected before January 2018. When it is launched, Ledaga will be available as a 160 μg/g gel.
Phase 2 study
The authorization of hybrid medicines depends partly on the results of tests on the reference medicine and partly on new data from clinical trials.
The marketing authorization for Ledaga is based, in part, on results of a multicenter, randomized, observer-blinded, active-controlled study of patients with stage I and IIA MF. Results from this phase 2 study were published in JAMA Dermatology.
The study enrolled 260 MF patients who were randomized 1:1 to receive topical treatment with 0.02% chlormethine gel (Ledaga) or compounded control—0.02% chlormethine compounded in Aquaphor® ointment—once daily for up to 12 months.
A response was defined as at least a 50% improvement in the baseline Composite Assessment of Index Lesion Severity score.
In the intent-to-treat population, 59% (76/130) of patients who received Ledaga achieved a clinical response, compared to 48% (62/130) of patients treated with the compounded control. The rate of complete response was 14% (n=18) and 12% (n=15), respectively.
Patients who were treated for at least 6 months were included in the efficacy-evaluable population. In this population, 77% (69/90) of patients who received Ledaga achieved a clinical response, compared to 59% (56/95) of patients treated with the compounded control. The rate of complete response was 19% (n=17) and 15% (n=14), respectively.
Reductions in mean lesion severity were seen as early as 4 weeks into the study, with further reductions observed with continuing therapy. The time to first confirmed response favored Ledaga.
The most frequent adverse reactions reported with Ledaga were skin-related—dermatitis (55%; eg, skin irritation, erythema, rash, urticaria, skin-burning sensation, skin pain), pruritus (20%), skin infections (12%), skin ulceration and blistering (6%), and skin hyperpigmentation (6%).
No systemic absorption of chlormethine was detected with treatment.
The European Commission has granted marketing authorization for chlormethine gel (Ledaga®) as a treatment for adults with mycosis fungoides (MF), but the product is not expected to be available until next year.
Ledaga is a hybrid medicine of Caryolysine, which has been approved for use in the European Union since 1946.
Hybrid medicines have a different strength, are administered differently, or have a different indication from the reference medicine.
Ledaga contains the same active substance as Caryolysine—chlormethine, a bifunctional alkylating agent that inhibits rapidly proliferating cells—but Ledaga is a gel intended for cutaneous use.
Actelion Pharmaceuticals Ltd, the company developing Ledaga, has agreed to fulfill a list of post-approval measures for the product proposed by the European Medicines Agency’s Committee for Medicinal Products for Human Use.
Subject to fulfilling the agreed commitments and achieving market access in various countries, a potential first European launch of Ledaga is not expected before January 2018. When it is launched, Ledaga will be available as a 160 μg/g gel.
Phase 2 study
The authorization of hybrid medicines depends partly on the results of tests on the reference medicine and partly on new data from clinical trials.
The marketing authorization for Ledaga is based, in part, on results of a multicenter, randomized, observer-blinded, active-controlled study of patients with stage I and IIA MF. Results from this phase 2 study were published in JAMA Dermatology.
The study enrolled 260 MF patients who were randomized 1:1 to receive topical treatment with 0.02% chlormethine gel (Ledaga) or compounded control—0.02% chlormethine compounded in Aquaphor® ointment—once daily for up to 12 months.
A response was defined as at least a 50% improvement in the baseline Composite Assessment of Index Lesion Severity score.
In the intent-to-treat population, 59% (76/130) of patients who received Ledaga achieved a clinical response, compared to 48% (62/130) of patients treated with the compounded control. The rate of complete response was 14% (n=18) and 12% (n=15), respectively.
Patients who were treated for at least 6 months were included in the efficacy-evaluable population. In this population, 77% (69/90) of patients who received Ledaga achieved a clinical response, compared to 59% (56/95) of patients treated with the compounded control. The rate of complete response was 19% (n=17) and 15% (n=14), respectively.
Reductions in mean lesion severity were seen as early as 4 weeks into the study, with further reductions observed with continuing therapy. The time to first confirmed response favored Ledaga.
The most frequent adverse reactions reported with Ledaga were skin-related—dermatitis (55%; eg, skin irritation, erythema, rash, urticaria, skin-burning sensation, skin pain), pruritus (20%), skin infections (12%), skin ulceration and blistering (6%), and skin hyperpigmentation (6%).
No systemic absorption of chlormethine was detected with treatment.
Pathogenesis of breast-implant-associated ALCL
SAN FRANCISCO—A small study suggests an abnormal immune response characterized by the production of interleukin-13 (IL-13) underlies the pathogenesis of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).
The immune response appears to be directed toward bacterial antigens on the surface of the breast implants.
Marshall E. Kadin, MD, of Roger Williams Medical Center in Providence, Rhode Island, presented these findings at the 9th Annual T-cell Lymphoma Forum.
Dr Kadin noted that BIA-ALCL is a rare type of CD30+ T-cell ALCL that has been reported in more than 200 women worldwide.
Although a cause-and-effect relationship between breast implants and BIA-ALCL has been suggested, the underlying pathogenesis of this malignancy is unclear.
A bacterial biofilm containing gram-negative bacilli has been detected in breast implants from patients with BIA-ALCL.
Therefore, Dr Kadin and his colleagues hypothesized that an immune response toward the bacterial antigens may mediate the pathogenesis of BIA-ALCL.
The researchers studied 13 clinical samples of breast implant capsules and regional lymph nodes from 4 patients with BIA-ALCL, 7 patients with systemic ALCL, and 1 patient with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).
Immunohistochemistry was used to determine the presence of IL-13, IL-4, GATA3, and immunoglobulin E (IgE) in these samples.
All clinical samples of anaplastic cells from breast implant capsules tested positive for the presence of IL-13 (13/13). GATA3 was expressed in most anaplastic cell samples (12/13), and IL-4 expression was found in some anaplastic cell samples (6/13). IL-13 and GATA3 expression were observed in some intra-capsular small lymphocytes.
While IL-13 was also detected in BIA-ALCL cell lines, it was not found in 4 of the 7 systemic ALCL cases or the PTCL-NOS case.
Dr Kadin said the lack of IL-13 receptor expression in BIA-ALCL cell lines suggests that IL-13 is not an autocrine growth factor for BIA-ALCL, and its expression is most likely associated with an allergic immune response.
IL-13 is known to induce immunoglobulin class switching in plasma cells to produce IgE. H&E and Giemsa staining of the BIA-ALCL tumor tissue and involved regional lymph nodes revealed IgE and eosinophils on the surface of mast cells and follicular dendritic cells.
Taken together, these data point to an allergic reaction in breast implant capsules of BIA-ALCL.
Dr Kadin was hopeful that these findings could be extrapolated to prevent BIA-ALCL by identifying individuals at higher risk for developing the disease.
The next step for this research is to decipher the role of bacterial antigens in mediating the immune response and whether women who develop BIA-ALCL have a significant increase in other atopic conditions.
SAN FRANCISCO—A small study suggests an abnormal immune response characterized by the production of interleukin-13 (IL-13) underlies the pathogenesis of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).
The immune response appears to be directed toward bacterial antigens on the surface of the breast implants.
Marshall E. Kadin, MD, of Roger Williams Medical Center in Providence, Rhode Island, presented these findings at the 9th Annual T-cell Lymphoma Forum.
Dr Kadin noted that BIA-ALCL is a rare type of CD30+ T-cell ALCL that has been reported in more than 200 women worldwide.
Although a cause-and-effect relationship between breast implants and BIA-ALCL has been suggested, the underlying pathogenesis of this malignancy is unclear.
A bacterial biofilm containing gram-negative bacilli has been detected in breast implants from patients with BIA-ALCL.
Therefore, Dr Kadin and his colleagues hypothesized that an immune response toward the bacterial antigens may mediate the pathogenesis of BIA-ALCL.
The researchers studied 13 clinical samples of breast implant capsules and regional lymph nodes from 4 patients with BIA-ALCL, 7 patients with systemic ALCL, and 1 patient with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).
Immunohistochemistry was used to determine the presence of IL-13, IL-4, GATA3, and immunoglobulin E (IgE) in these samples.
All clinical samples of anaplastic cells from breast implant capsules tested positive for the presence of IL-13 (13/13). GATA3 was expressed in most anaplastic cell samples (12/13), and IL-4 expression was found in some anaplastic cell samples (6/13). IL-13 and GATA3 expression were observed in some intra-capsular small lymphocytes.
While IL-13 was also detected in BIA-ALCL cell lines, it was not found in 4 of the 7 systemic ALCL cases or the PTCL-NOS case.
Dr Kadin said the lack of IL-13 receptor expression in BIA-ALCL cell lines suggests that IL-13 is not an autocrine growth factor for BIA-ALCL, and its expression is most likely associated with an allergic immune response.
IL-13 is known to induce immunoglobulin class switching in plasma cells to produce IgE. H&E and Giemsa staining of the BIA-ALCL tumor tissue and involved regional lymph nodes revealed IgE and eosinophils on the surface of mast cells and follicular dendritic cells.
Taken together, these data point to an allergic reaction in breast implant capsules of BIA-ALCL.
Dr Kadin was hopeful that these findings could be extrapolated to prevent BIA-ALCL by identifying individuals at higher risk for developing the disease.
The next step for this research is to decipher the role of bacterial antigens in mediating the immune response and whether women who develop BIA-ALCL have a significant increase in other atopic conditions.
SAN FRANCISCO—A small study suggests an abnormal immune response characterized by the production of interleukin-13 (IL-13) underlies the pathogenesis of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).
The immune response appears to be directed toward bacterial antigens on the surface of the breast implants.
Marshall E. Kadin, MD, of Roger Williams Medical Center in Providence, Rhode Island, presented these findings at the 9th Annual T-cell Lymphoma Forum.
Dr Kadin noted that BIA-ALCL is a rare type of CD30+ T-cell ALCL that has been reported in more than 200 women worldwide.
Although a cause-and-effect relationship between breast implants and BIA-ALCL has been suggested, the underlying pathogenesis of this malignancy is unclear.
A bacterial biofilm containing gram-negative bacilli has been detected in breast implants from patients with BIA-ALCL.
Therefore, Dr Kadin and his colleagues hypothesized that an immune response toward the bacterial antigens may mediate the pathogenesis of BIA-ALCL.
The researchers studied 13 clinical samples of breast implant capsules and regional lymph nodes from 4 patients with BIA-ALCL, 7 patients with systemic ALCL, and 1 patient with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).
Immunohistochemistry was used to determine the presence of IL-13, IL-4, GATA3, and immunoglobulin E (IgE) in these samples.
All clinical samples of anaplastic cells from breast implant capsules tested positive for the presence of IL-13 (13/13). GATA3 was expressed in most anaplastic cell samples (12/13), and IL-4 expression was found in some anaplastic cell samples (6/13). IL-13 and GATA3 expression were observed in some intra-capsular small lymphocytes.
While IL-13 was also detected in BIA-ALCL cell lines, it was not found in 4 of the 7 systemic ALCL cases or the PTCL-NOS case.
Dr Kadin said the lack of IL-13 receptor expression in BIA-ALCL cell lines suggests that IL-13 is not an autocrine growth factor for BIA-ALCL, and its expression is most likely associated with an allergic immune response.
IL-13 is known to induce immunoglobulin class switching in plasma cells to produce IgE. H&E and Giemsa staining of the BIA-ALCL tumor tissue and involved regional lymph nodes revealed IgE and eosinophils on the surface of mast cells and follicular dendritic cells.
Taken together, these data point to an allergic reaction in breast implant capsules of BIA-ALCL.
Dr Kadin was hopeful that these findings could be extrapolated to prevent BIA-ALCL by identifying individuals at higher risk for developing the disease.
The next step for this research is to decipher the role of bacterial antigens in mediating the immune response and whether women who develop BIA-ALCL have a significant increase in other atopic conditions.
Study sheds light on genetic landscape of HSTL
SAN FRANCISCO—Researchers say they have identified new driver genes and oncogenic pathways in hepatosplenic T-cell lymphoma (HSTL).
The team found that SETD2, a known tumor suppressor, was the most frequently silenced gene in HSTL.
The researchers also found evidence suggesting the JAK-STAT and PI3K pathways could be therapeutic targets in HSTL.
Sandeep Dave, MD, of Duke University in Durham, North Carolina, presented these findings at the 9th Annual T-cell Lymphoma Forum. Results from this research were also published in Cancer Discovery.
The researchers collected complete clinical data on 68 HSTL cases, including 20 with normal DNA. The team performed whole-genome sequencing, bioinformatics analysis, and biological characterization of these cases.
“This is the largest group of HSTL cases ever described, and the data implicate new driver genes and oncogenic pathways for the first time in HSTL,” Dr Dave said.
The data revealed that the most commonly mutated group of genes in HSTL are chromatin modifiers (SETD2, INO80, ARID1B, TET3, and SMARCA2) and signaling pathway genes (STAT5B, STAT3, and PIK3CD). Among these, STAT3, PIK3CD, and SETD2 showed the highest proportion of clonal events.
On the other hand, mutations in EZH2, KRAS, and TP53 were less frequently observed.
Common genetic abnormalities in HSTL include copy number alterations in chromosome 7, trisomy 8, loss of 10p, and gain of 1q.
A comparison of the frequencies of recurrently mutated genes in HSTL with other lymphomas demonstrated the genetically distinct profile of HSTL, wherein mutations in SETD2, INO80, TET3, and STAT5B occurred exclusively in HSTL.
SETD2, a histone lysine methyltransferase and a known tumor suppressor, was identified as the most frequently silenced gene in HSTL.
So the researchers investigated the biological effects of SETD2 loss in HSTL cells and a knockout mouse model.
While loss of SETD2 in HSTL cells resulted in increased cell proliferation, in vivo knockdown of SETD2 led to expansion of γ-δ T cells and a reduction in α-β T cells. A majority of HSTLs are known to arise predominantly from γ-δ T cells.
“These results implicate SETD2 in HSTL oncogenesis and T-cell development,” Dr Dave said.
He and his colleagues also found that constitutive activation of the JAK-STAT and PI3K pathways in HSTL cells was associated with increased proliferation, and inhibition of these pathways led to reduced survival of HSTL cells. This suggests that agents targeting these pathways might be effective in treating HSTL.
SAN FRANCISCO—Researchers say they have identified new driver genes and oncogenic pathways in hepatosplenic T-cell lymphoma (HSTL).
The team found that SETD2, a known tumor suppressor, was the most frequently silenced gene in HSTL.
The researchers also found evidence suggesting the JAK-STAT and PI3K pathways could be therapeutic targets in HSTL.
Sandeep Dave, MD, of Duke University in Durham, North Carolina, presented these findings at the 9th Annual T-cell Lymphoma Forum. Results from this research were also published in Cancer Discovery.
The researchers collected complete clinical data on 68 HSTL cases, including 20 with normal DNA. The team performed whole-genome sequencing, bioinformatics analysis, and biological characterization of these cases.
“This is the largest group of HSTL cases ever described, and the data implicate new driver genes and oncogenic pathways for the first time in HSTL,” Dr Dave said.
The data revealed that the most commonly mutated group of genes in HSTL are chromatin modifiers (SETD2, INO80, ARID1B, TET3, and SMARCA2) and signaling pathway genes (STAT5B, STAT3, and PIK3CD). Among these, STAT3, PIK3CD, and SETD2 showed the highest proportion of clonal events.
On the other hand, mutations in EZH2, KRAS, and TP53 were less frequently observed.
Common genetic abnormalities in HSTL include copy number alterations in chromosome 7, trisomy 8, loss of 10p, and gain of 1q.
A comparison of the frequencies of recurrently mutated genes in HSTL with other lymphomas demonstrated the genetically distinct profile of HSTL, wherein mutations in SETD2, INO80, TET3, and STAT5B occurred exclusively in HSTL.
SETD2, a histone lysine methyltransferase and a known tumor suppressor, was identified as the most frequently silenced gene in HSTL.
So the researchers investigated the biological effects of SETD2 loss in HSTL cells and a knockout mouse model.
While loss of SETD2 in HSTL cells resulted in increased cell proliferation, in vivo knockdown of SETD2 led to expansion of γ-δ T cells and a reduction in α-β T cells. A majority of HSTLs are known to arise predominantly from γ-δ T cells.
“These results implicate SETD2 in HSTL oncogenesis and T-cell development,” Dr Dave said.
He and his colleagues also found that constitutive activation of the JAK-STAT and PI3K pathways in HSTL cells was associated with increased proliferation, and inhibition of these pathways led to reduced survival of HSTL cells. This suggests that agents targeting these pathways might be effective in treating HSTL.
SAN FRANCISCO—Researchers say they have identified new driver genes and oncogenic pathways in hepatosplenic T-cell lymphoma (HSTL).
The team found that SETD2, a known tumor suppressor, was the most frequently silenced gene in HSTL.
The researchers also found evidence suggesting the JAK-STAT and PI3K pathways could be therapeutic targets in HSTL.
Sandeep Dave, MD, of Duke University in Durham, North Carolina, presented these findings at the 9th Annual T-cell Lymphoma Forum. Results from this research were also published in Cancer Discovery.
The researchers collected complete clinical data on 68 HSTL cases, including 20 with normal DNA. The team performed whole-genome sequencing, bioinformatics analysis, and biological characterization of these cases.
“This is the largest group of HSTL cases ever described, and the data implicate new driver genes and oncogenic pathways for the first time in HSTL,” Dr Dave said.
The data revealed that the most commonly mutated group of genes in HSTL are chromatin modifiers (SETD2, INO80, ARID1B, TET3, and SMARCA2) and signaling pathway genes (STAT5B, STAT3, and PIK3CD). Among these, STAT3, PIK3CD, and SETD2 showed the highest proportion of clonal events.
On the other hand, mutations in EZH2, KRAS, and TP53 were less frequently observed.
Common genetic abnormalities in HSTL include copy number alterations in chromosome 7, trisomy 8, loss of 10p, and gain of 1q.
A comparison of the frequencies of recurrently mutated genes in HSTL with other lymphomas demonstrated the genetically distinct profile of HSTL, wherein mutations in SETD2, INO80, TET3, and STAT5B occurred exclusively in HSTL.
SETD2, a histone lysine methyltransferase and a known tumor suppressor, was identified as the most frequently silenced gene in HSTL.
So the researchers investigated the biological effects of SETD2 loss in HSTL cells and a knockout mouse model.
While loss of SETD2 in HSTL cells resulted in increased cell proliferation, in vivo knockdown of SETD2 led to expansion of γ-δ T cells and a reduction in α-β T cells. A majority of HSTLs are known to arise predominantly from γ-δ T cells.
“These results implicate SETD2 in HSTL oncogenesis and T-cell development,” Dr Dave said.
He and his colleagues also found that constitutive activation of the JAK-STAT and PI3K pathways in HSTL cells was associated with increased proliferation, and inhibition of these pathways led to reduced survival of HSTL cells. This suggests that agents targeting these pathways might be effective in treating HSTL.