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Cancer risk, burden expected to shift in HIV population
WASHINGTON, DC—New research suggests HIV-positive adults in the US will see a shift in cancer risk and burden in the coming years.
The study indicates that, through 2030, people living with HIV will see a decrease in AIDS-defining cancers, such as non-Hodgkin lymphoma (NHL) and Kaposi sarcoma.
But this group will also see an increase in cancers not linked to AIDS, such as prostate and liver cancers.
Researchers made these projections in a presentation at the AACR Annual Meeting 2017 (abstract 5302).
“Declines in cancer incidence rates, particularly for AIDS-defining cancers, are likely driven by widespread treatment with modern antiretroviral therapies, which reduce immune suppression and decrease risk of some cancers,” said Jessica Y. Islam, a doctoral student at the University of North Carolina Gillings School of Global Public Health in Chapel Hill.
She and her collaborators estimated future cancer risk and burden for HIV-positive people using age-specific cancer incidence data from the National Cancer Institute HIV/AIDS Cancer Match (HACM) Study, and projected HIV prevalence data from the Centers for Disease Control and Prevention.
Cancer incidence
From 2000 to 2012, there were 23,907 cancers reported in 463,300 HIV-infected adults in the HACM Study. Based on trends in this study, the researchers made projections for cancer incidence through 2030.
They projected that HIV-positive adults of all ages will see a significant decrease over time in the incidence of NHL, Kaposi sarcoma, cervical cancer, anal cancer among men who have sex with men (MSM), lung cancer, and Hodgkin lymphoma.
Patients age 65 and older will see a significant decrease in colon cancer incidence over time. However, there will be no significant change for patients younger than 65.
HIV-positive adults of all ages will see no significant change over time in the incidence of liver cancer, oral cavity cancer, anal cancer among non-MSMs, and breast cancer.
The incidence of prostate cancer will increase significantly among patients ages 35 to 44 and among patients ages 45 to 64.
Cancer burden
The researchers said the number of adults living with HIV in the US is projected to increase from 1.06 million in 2006 to 1.17 million in 2018, but it is expected to decline to 1.09 million in 2030.
The team noted that, in 2006, there were an estimated 8241 cancers in patients with HIV—3522 AIDS-defining cancers and 4719 malignancies not associated with AIDS.
In 2030, the total number of cancers in the HIV-positive population is projected to be 6692, with decreases in AIDS-defining cancers (n=716) and increases in other cancers (n=5976) from the 2006 data.
In 2010, the most common cancers among HIV-positive patients were estimated to be NHL (n=1488), Kaposi sarcoma (n=1133), and lung cancer (n=815).
But in 2030, the most common cancers are projected to be prostate (n=1587), lung (n=1027), and liver cancers (n=483).
“It is critical to understand both incidence rates and burden over time, as rates capture changes in cancer risk, and burden quantifies the actual number of cancer cases expected to occur,” said study investigator Meredith S. Shiels, PhD, of the National Cancer Institute in Bethesda, Maryland.
“For example, lung cancer rates are expected to decrease in the future, but the burden is expected to increase due to the growing number of older people living with HIV.” 
WASHINGTON, DC—New research suggests HIV-positive adults in the US will see a shift in cancer risk and burden in the coming years.
The study indicates that, through 2030, people living with HIV will see a decrease in AIDS-defining cancers, such as non-Hodgkin lymphoma (NHL) and Kaposi sarcoma.
But this group will also see an increase in cancers not linked to AIDS, such as prostate and liver cancers.
Researchers made these projections in a presentation at the AACR Annual Meeting 2017 (abstract 5302).
“Declines in cancer incidence rates, particularly for AIDS-defining cancers, are likely driven by widespread treatment with modern antiretroviral therapies, which reduce immune suppression and decrease risk of some cancers,” said Jessica Y. Islam, a doctoral student at the University of North Carolina Gillings School of Global Public Health in Chapel Hill.
She and her collaborators estimated future cancer risk and burden for HIV-positive people using age-specific cancer incidence data from the National Cancer Institute HIV/AIDS Cancer Match (HACM) Study, and projected HIV prevalence data from the Centers for Disease Control and Prevention.
Cancer incidence
From 2000 to 2012, there were 23,907 cancers reported in 463,300 HIV-infected adults in the HACM Study. Based on trends in this study, the researchers made projections for cancer incidence through 2030.
They projected that HIV-positive adults of all ages will see a significant decrease over time in the incidence of NHL, Kaposi sarcoma, cervical cancer, anal cancer among men who have sex with men (MSM), lung cancer, and Hodgkin lymphoma.
Patients age 65 and older will see a significant decrease in colon cancer incidence over time. However, there will be no significant change for patients younger than 65.
HIV-positive adults of all ages will see no significant change over time in the incidence of liver cancer, oral cavity cancer, anal cancer among non-MSMs, and breast cancer.
The incidence of prostate cancer will increase significantly among patients ages 35 to 44 and among patients ages 45 to 64.
Cancer burden
The researchers said the number of adults living with HIV in the US is projected to increase from 1.06 million in 2006 to 1.17 million in 2018, but it is expected to decline to 1.09 million in 2030.
The team noted that, in 2006, there were an estimated 8241 cancers in patients with HIV—3522 AIDS-defining cancers and 4719 malignancies not associated with AIDS.
In 2030, the total number of cancers in the HIV-positive population is projected to be 6692, with decreases in AIDS-defining cancers (n=716) and increases in other cancers (n=5976) from the 2006 data.
In 2010, the most common cancers among HIV-positive patients were estimated to be NHL (n=1488), Kaposi sarcoma (n=1133), and lung cancer (n=815).
But in 2030, the most common cancers are projected to be prostate (n=1587), lung (n=1027), and liver cancers (n=483).
“It is critical to understand both incidence rates and burden over time, as rates capture changes in cancer risk, and burden quantifies the actual number of cancer cases expected to occur,” said study investigator Meredith S. Shiels, PhD, of the National Cancer Institute in Bethesda, Maryland.
“For example, lung cancer rates are expected to decrease in the future, but the burden is expected to increase due to the growing number of older people living with HIV.”
WASHINGTON, DC—New research suggests HIV-positive adults in the US will see a shift in cancer risk and burden in the coming years.
The study indicates that, through 2030, people living with HIV will see a decrease in AIDS-defining cancers, such as non-Hodgkin lymphoma (NHL) and Kaposi sarcoma.
But this group will also see an increase in cancers not linked to AIDS, such as prostate and liver cancers.
Researchers made these projections in a presentation at the AACR Annual Meeting 2017 (abstract 5302).
“Declines in cancer incidence rates, particularly for AIDS-defining cancers, are likely driven by widespread treatment with modern antiretroviral therapies, which reduce immune suppression and decrease risk of some cancers,” said Jessica Y. Islam, a doctoral student at the University of North Carolina Gillings School of Global Public Health in Chapel Hill.
She and her collaborators estimated future cancer risk and burden for HIV-positive people using age-specific cancer incidence data from the National Cancer Institute HIV/AIDS Cancer Match (HACM) Study, and projected HIV prevalence data from the Centers for Disease Control and Prevention.
Cancer incidence
From 2000 to 2012, there were 23,907 cancers reported in 463,300 HIV-infected adults in the HACM Study. Based on trends in this study, the researchers made projections for cancer incidence through 2030.
They projected that HIV-positive adults of all ages will see a significant decrease over time in the incidence of NHL, Kaposi sarcoma, cervical cancer, anal cancer among men who have sex with men (MSM), lung cancer, and Hodgkin lymphoma.
Patients age 65 and older will see a significant decrease in colon cancer incidence over time. However, there will be no significant change for patients younger than 65.
HIV-positive adults of all ages will see no significant change over time in the incidence of liver cancer, oral cavity cancer, anal cancer among non-MSMs, and breast cancer.
The incidence of prostate cancer will increase significantly among patients ages 35 to 44 and among patients ages 45 to 64.
Cancer burden
The researchers said the number of adults living with HIV in the US is projected to increase from 1.06 million in 2006 to 1.17 million in 2018, but it is expected to decline to 1.09 million in 2030.
The team noted that, in 2006, there were an estimated 8241 cancers in patients with HIV—3522 AIDS-defining cancers and 4719 malignancies not associated with AIDS.
In 2030, the total number of cancers in the HIV-positive population is projected to be 6692, with decreases in AIDS-defining cancers (n=716) and increases in other cancers (n=5976) from the 2006 data.
In 2010, the most common cancers among HIV-positive patients were estimated to be NHL (n=1488), Kaposi sarcoma (n=1133), and lung cancer (n=815).
But in 2030, the most common cancers are projected to be prostate (n=1587), lung (n=1027), and liver cancers (n=483).
“It is critical to understand both incidence rates and burden over time, as rates capture changes in cancer risk, and burden quantifies the actual number of cancer cases expected to occur,” said study investigator Meredith S. Shiels, PhD, of the National Cancer Institute in Bethesda, Maryland.
“For example, lung cancer rates are expected to decrease in the future, but the burden is expected to increase due to the growing number of older people living with HIV.”
Factor IX therapy seems safe, effective in young kids
SCOTTSDALE, ARIZONA—The recombinant factor IX product trenonacog alfa appears safe and effective for previously treated patients with hemophilia B who are younger than 12 years of age, according to researchers.
The team conducted a pooled analysis of 2 studies, which included a total of 12 patients.
The median annualized bleeding rate (ABR) was low among patients who received trenonacog alfa as prophylaxis.
Among all patients, 72% of bleeding episodes were resolved with a single infusion of trenonacog alfa.
None of the patients developed factor IX inhibitors, and treatment-related adverse events consisted of fever and hyperhidrosis.
These results were presented in a poster at the Hemostasis and Thrombosis Research Society 2017 Scientific Symposium.
The research was conducted by employees of Aptevo Therapeutics, the company marketing trenonacog alfa as IXINITY®. The poster is available on the company’s website.
The researchers conducted a pooled analysis of 2 prospective, non-randomized studies of 12 children with hemophilia B under the age of 12.
The patients’ median age was 9.5 (range, 2-11). All patients were male. Half were Asian, 3 were white, 2 were Pacific Islanders, and 1 belonged to an “other” racial/ethnic group.
Eleven patients received trenonacog alfa as prophylaxis, and 1 patient received the treatment on demand.
Among the patients on prophylaxis, the median number of exposure days was 254 (range, 111-404), and the median dose per infusion was 75.3 IU/kg (range, 25.3-111.0).
For the patients on prophylaxis, the median number of bleeding episodes was 1.0 (range, 0-11), and the median ABR was 0.3 (range, 0-4.0). Two patients had no bleeding episodes.
The patient who received trenonacog alfa on demand had 23 bleeding episodes and an ABR of 11.1.
There were a total of 61 bleeding episodes in this study. Most (72%, n=44) resolved after 1 infusion of trenonacog alfa, and 10% (n=6) resolved without any infusions.
Eight percent of the bleeding episodes (n=5) required 2 infusions of trenonacog alfa, and 10% (n=6) required 3, 4, or 5 infusions.
Adverse events thought to be related to trenonacog alfa were hyperhidrosis and fever in 1 patient, and hyperhidrosis in another patient.
SCOTTSDALE, ARIZONA—The recombinant factor IX product trenonacog alfa appears safe and effective for previously treated patients with hemophilia B who are younger than 12 years of age, according to researchers.
The team conducted a pooled analysis of 2 studies, which included a total of 12 patients.
The median annualized bleeding rate (ABR) was low among patients who received trenonacog alfa as prophylaxis.
Among all patients, 72% of bleeding episodes were resolved with a single infusion of trenonacog alfa.
None of the patients developed factor IX inhibitors, and treatment-related adverse events consisted of fever and hyperhidrosis.
These results were presented in a poster at the Hemostasis and Thrombosis Research Society 2017 Scientific Symposium.
The research was conducted by employees of Aptevo Therapeutics, the company marketing trenonacog alfa as IXINITY®. The poster is available on the company’s website.
The researchers conducted a pooled analysis of 2 prospective, non-randomized studies of 12 children with hemophilia B under the age of 12.
The patients’ median age was 9.5 (range, 2-11). All patients were male. Half were Asian, 3 were white, 2 were Pacific Islanders, and 1 belonged to an “other” racial/ethnic group.
Eleven patients received trenonacog alfa as prophylaxis, and 1 patient received the treatment on demand.
Among the patients on prophylaxis, the median number of exposure days was 254 (range, 111-404), and the median dose per infusion was 75.3 IU/kg (range, 25.3-111.0).
For the patients on prophylaxis, the median number of bleeding episodes was 1.0 (range, 0-11), and the median ABR was 0.3 (range, 0-4.0). Two patients had no bleeding episodes.
The patient who received trenonacog alfa on demand had 23 bleeding episodes and an ABR of 11.1.
There were a total of 61 bleeding episodes in this study. Most (72%, n=44) resolved after 1 infusion of trenonacog alfa, and 10% (n=6) resolved without any infusions.
Eight percent of the bleeding episodes (n=5) required 2 infusions of trenonacog alfa, and 10% (n=6) required 3, 4, or 5 infusions.
Adverse events thought to be related to trenonacog alfa were hyperhidrosis and fever in 1 patient, and hyperhidrosis in another patient.
SCOTTSDALE, ARIZONA—The recombinant factor IX product trenonacog alfa appears safe and effective for previously treated patients with hemophilia B who are younger than 12 years of age, according to researchers.
The team conducted a pooled analysis of 2 studies, which included a total of 12 patients.
The median annualized bleeding rate (ABR) was low among patients who received trenonacog alfa as prophylaxis.
Among all patients, 72% of bleeding episodes were resolved with a single infusion of trenonacog alfa.
None of the patients developed factor IX inhibitors, and treatment-related adverse events consisted of fever and hyperhidrosis.
These results were presented in a poster at the Hemostasis and Thrombosis Research Society 2017 Scientific Symposium.
The research was conducted by employees of Aptevo Therapeutics, the company marketing trenonacog alfa as IXINITY®. The poster is available on the company’s website.
The researchers conducted a pooled analysis of 2 prospective, non-randomized studies of 12 children with hemophilia B under the age of 12.
The patients’ median age was 9.5 (range, 2-11). All patients were male. Half were Asian, 3 were white, 2 were Pacific Islanders, and 1 belonged to an “other” racial/ethnic group.
Eleven patients received trenonacog alfa as prophylaxis, and 1 patient received the treatment on demand.
Among the patients on prophylaxis, the median number of exposure days was 254 (range, 111-404), and the median dose per infusion was 75.3 IU/kg (range, 25.3-111.0).
For the patients on prophylaxis, the median number of bleeding episodes was 1.0 (range, 0-11), and the median ABR was 0.3 (range, 0-4.0). Two patients had no bleeding episodes.
The patient who received trenonacog alfa on demand had 23 bleeding episodes and an ABR of 11.1.
There were a total of 61 bleeding episodes in this study. Most (72%, n=44) resolved after 1 infusion of trenonacog alfa, and 10% (n=6) resolved without any infusions.
Eight percent of the bleeding episodes (n=5) required 2 infusions of trenonacog alfa, and 10% (n=6) required 3, 4, or 5 infusions.
Adverse events thought to be related to trenonacog alfa were hyperhidrosis and fever in 1 patient, and hyperhidrosis in another patient.
Weighing risks, benefits of autologous HSCT in MM
The use of autologous transplant after a 3-drug induction regimen for multiple myeloma (MM) prolongs progression-free survival (PFS) but not overall survival (OS), according to new research.
In a phase 3 trial, newly diagnosed MM patients who received lenalidomide, bortezomib, and dexamethasone (RVD) followed by an autologous hematopoietic stem cell transplant (HSCT) had significantly better PFS but similar OS when compared to patients who only received RVD.
In addition, HSCT recipients had significantly higher rates of high-grade blood and lymphatic system disorders, gastrointestinal events, and infections.
The study also showed that OS outcomes were similar for patients who received HSCT after completing treatment with RVD and patients who were in the RVD-only treatment arm but underwent HSCT later, as salvage therapy.
Researchers believe this suggests MM patients can potentially choose when to undergo a transplant.
The team reported their findings in NEJM. The study was supported by grants from Celgene and Janssen and by funds from the French Ministry of Health Programme Hospitalier de Recherche Clinique and from the French National Research Agency.
“Over the past decade, drugs that modulate the immune system and agents known as proteasome inhibitors have shown a great deal of promise in patients with multiple myeloma, when used in combination with chemotherapy,” said study author Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“This led us to propose that these combinations could be used selectively with established modalities such as transplant for patients with newly diagnosed myeloma, and this, in turn, raised questions about where and how transplant should be fit into the therapeutic paradigm. Our trial sought to comprehensively address these issues in a prospective fashion, and provide a foundation for future studies as the next generation of agents, such as monoclonal antibodies, impact the field.”
The study enrolled 700 adult patients under the age of 65 who were newly diagnosed with MM. They were treated at 69 centers in France, Belgium, and Switzerland.
The patients were randomized to 2 treatment arms. Both groups received 3 initial cycles of RVD.
One group then received 5 more cycles of RVD. The other received high-dose chemotherapy (melphalan) followed by an autologous HSCT and 2 additional cycles of RVD.
Patients in both groups then received lenalidomide as maintenance therapy for 1 year or until they progressed, experienced unacceptable adverse events (AEs), or withdrew consent.
Response and survival
The complete response rate was significantly higher in the HSCT arm than the RVD-alone arm—59% and 48%, respectively (P=0.03).
And there was a significantly higher percentage of patients who were negative for minimal residual disease in the HSCT arm than in the RVD arm—79% and 65%, respectively (P<0.001).
The median PFS was significantly longer in the HSCT arm than the RVD arm—50 months and 36 months, respectively (P<0.001). The researchers said this benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk.
There was no significant between-group difference in the rate of OS at 4 years, which was 81% in the HSCT arm and 82% in the RVD arm.
Subsequent therapy
In the RVD arm, 207 patients progressed, and 172 received second-line therapy, which was followed by salvage HSCT in 136 patients (79%).
In the HSCT arm, 149 patients progressed, and 123 received second-line therapy, which was followed by a second HSCT in 21 patients (17%).
Safety
Nine percent of patients in the RVD arm and 11% in the HSCT arm discontinued treatment due to AEs. There were 2 treatment-related deaths in the RVD arm and 6 in the HSCT arm.
Grade 3/4 AEs with a significantly higher incidence in the HSCT arm than the RVD arm were blood and lymphatic system disorders (95% and 64%, respectively, P<0.001), gastrointestinal disorders (28% and 7%, respectively, P<0.001), and infections (20% and 9%, respectively, P<0.001).
Thirteen patients in the RVD arm and 17 in the HSCT arm had at least 1 invasive second primary malignancy (P=0.36). Acute myeloid leukemia occurred in 1 patient in the RVD arm and 4 in the HSCT arm (P=0.21).
The researchers said these results suggest the benefits of HSCT plus RVD must be weighed against the increased risk of toxicity associated with high-dose chemotherapy plus HSCT, particularly since HSCT after progression might be as effective as early HSCT for ensuring long-term OS.
The use of autologous transplant after a 3-drug induction regimen for multiple myeloma (MM) prolongs progression-free survival (PFS) but not overall survival (OS), according to new research.
In a phase 3 trial, newly diagnosed MM patients who received lenalidomide, bortezomib, and dexamethasone (RVD) followed by an autologous hematopoietic stem cell transplant (HSCT) had significantly better PFS but similar OS when compared to patients who only received RVD.
In addition, HSCT recipients had significantly higher rates of high-grade blood and lymphatic system disorders, gastrointestinal events, and infections.
The study also showed that OS outcomes were similar for patients who received HSCT after completing treatment with RVD and patients who were in the RVD-only treatment arm but underwent HSCT later, as salvage therapy.
Researchers believe this suggests MM patients can potentially choose when to undergo a transplant.
The team reported their findings in NEJM. The study was supported by grants from Celgene and Janssen and by funds from the French Ministry of Health Programme Hospitalier de Recherche Clinique and from the French National Research Agency.
“Over the past decade, drugs that modulate the immune system and agents known as proteasome inhibitors have shown a great deal of promise in patients with multiple myeloma, when used in combination with chemotherapy,” said study author Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“This led us to propose that these combinations could be used selectively with established modalities such as transplant for patients with newly diagnosed myeloma, and this, in turn, raised questions about where and how transplant should be fit into the therapeutic paradigm. Our trial sought to comprehensively address these issues in a prospective fashion, and provide a foundation for future studies as the next generation of agents, such as monoclonal antibodies, impact the field.”
The study enrolled 700 adult patients under the age of 65 who were newly diagnosed with MM. They were treated at 69 centers in France, Belgium, and Switzerland.
The patients were randomized to 2 treatment arms. Both groups received 3 initial cycles of RVD.
One group then received 5 more cycles of RVD. The other received high-dose chemotherapy (melphalan) followed by an autologous HSCT and 2 additional cycles of RVD.
Patients in both groups then received lenalidomide as maintenance therapy for 1 year or until they progressed, experienced unacceptable adverse events (AEs), or withdrew consent.
Response and survival
The complete response rate was significantly higher in the HSCT arm than the RVD-alone arm—59% and 48%, respectively (P=0.03).
And there was a significantly higher percentage of patients who were negative for minimal residual disease in the HSCT arm than in the RVD arm—79% and 65%, respectively (P<0.001).
The median PFS was significantly longer in the HSCT arm than the RVD arm—50 months and 36 months, respectively (P<0.001). The researchers said this benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk.
There was no significant between-group difference in the rate of OS at 4 years, which was 81% in the HSCT arm and 82% in the RVD arm.
Subsequent therapy
In the RVD arm, 207 patients progressed, and 172 received second-line therapy, which was followed by salvage HSCT in 136 patients (79%).
In the HSCT arm, 149 patients progressed, and 123 received second-line therapy, which was followed by a second HSCT in 21 patients (17%).
Safety
Nine percent of patients in the RVD arm and 11% in the HSCT arm discontinued treatment due to AEs. There were 2 treatment-related deaths in the RVD arm and 6 in the HSCT arm.
Grade 3/4 AEs with a significantly higher incidence in the HSCT arm than the RVD arm were blood and lymphatic system disorders (95% and 64%, respectively, P<0.001), gastrointestinal disorders (28% and 7%, respectively, P<0.001), and infections (20% and 9%, respectively, P<0.001).
Thirteen patients in the RVD arm and 17 in the HSCT arm had at least 1 invasive second primary malignancy (P=0.36). Acute myeloid leukemia occurred in 1 patient in the RVD arm and 4 in the HSCT arm (P=0.21).
The researchers said these results suggest the benefits of HSCT plus RVD must be weighed against the increased risk of toxicity associated with high-dose chemotherapy plus HSCT, particularly since HSCT after progression might be as effective as early HSCT for ensuring long-term OS.
The use of autologous transplant after a 3-drug induction regimen for multiple myeloma (MM) prolongs progression-free survival (PFS) but not overall survival (OS), according to new research.
In a phase 3 trial, newly diagnosed MM patients who received lenalidomide, bortezomib, and dexamethasone (RVD) followed by an autologous hematopoietic stem cell transplant (HSCT) had significantly better PFS but similar OS when compared to patients who only received RVD.
In addition, HSCT recipients had significantly higher rates of high-grade blood and lymphatic system disorders, gastrointestinal events, and infections.
The study also showed that OS outcomes were similar for patients who received HSCT after completing treatment with RVD and patients who were in the RVD-only treatment arm but underwent HSCT later, as salvage therapy.
Researchers believe this suggests MM patients can potentially choose when to undergo a transplant.
The team reported their findings in NEJM. The study was supported by grants from Celgene and Janssen and by funds from the French Ministry of Health Programme Hospitalier de Recherche Clinique and from the French National Research Agency.
“Over the past decade, drugs that modulate the immune system and agents known as proteasome inhibitors have shown a great deal of promise in patients with multiple myeloma, when used in combination with chemotherapy,” said study author Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“This led us to propose that these combinations could be used selectively with established modalities such as transplant for patients with newly diagnosed myeloma, and this, in turn, raised questions about where and how transplant should be fit into the therapeutic paradigm. Our trial sought to comprehensively address these issues in a prospective fashion, and provide a foundation for future studies as the next generation of agents, such as monoclonal antibodies, impact the field.”
The study enrolled 700 adult patients under the age of 65 who were newly diagnosed with MM. They were treated at 69 centers in France, Belgium, and Switzerland.
The patients were randomized to 2 treatment arms. Both groups received 3 initial cycles of RVD.
One group then received 5 more cycles of RVD. The other received high-dose chemotherapy (melphalan) followed by an autologous HSCT and 2 additional cycles of RVD.
Patients in both groups then received lenalidomide as maintenance therapy for 1 year or until they progressed, experienced unacceptable adverse events (AEs), or withdrew consent.
Response and survival
The complete response rate was significantly higher in the HSCT arm than the RVD-alone arm—59% and 48%, respectively (P=0.03).
And there was a significantly higher percentage of patients who were negative for minimal residual disease in the HSCT arm than in the RVD arm—79% and 65%, respectively (P<0.001).
The median PFS was significantly longer in the HSCT arm than the RVD arm—50 months and 36 months, respectively (P<0.001). The researchers said this benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk.
There was no significant between-group difference in the rate of OS at 4 years, which was 81% in the HSCT arm and 82% in the RVD arm.
Subsequent therapy
In the RVD arm, 207 patients progressed, and 172 received second-line therapy, which was followed by salvage HSCT in 136 patients (79%).
In the HSCT arm, 149 patients progressed, and 123 received second-line therapy, which was followed by a second HSCT in 21 patients (17%).
Safety
Nine percent of patients in the RVD arm and 11% in the HSCT arm discontinued treatment due to AEs. There were 2 treatment-related deaths in the RVD arm and 6 in the HSCT arm.
Grade 3/4 AEs with a significantly higher incidence in the HSCT arm than the RVD arm were blood and lymphatic system disorders (95% and 64%, respectively, P<0.001), gastrointestinal disorders (28% and 7%, respectively, P<0.001), and infections (20% and 9%, respectively, P<0.001).
Thirteen patients in the RVD arm and 17 in the HSCT arm had at least 1 invasive second primary malignancy (P=0.36). Acute myeloid leukemia occurred in 1 patient in the RVD arm and 4 in the HSCT arm (P=0.21).
The researchers said these results suggest the benefits of HSCT plus RVD must be weighed against the increased risk of toxicity associated with high-dose chemotherapy plus HSCT, particularly since HSCT after progression might be as effective as early HSCT for ensuring long-term OS.
Parental smoking linked to genetic changes in kids with ALL
Smoking by either parent helps promote genetic deletions in children that are associated with the development and progression of acute lymphoblastic leukemia (ALL), according to a study published in Cancer Research.
The strongest associations in this study were found in children whose parents smoked while the children were in utero and during their infancy.
However, the genetic deletions were also noted in the offspring of parents who may have quit smoking even before conception.
The link between ALL and parental smoking has already been established, but this is the first study that points to specific genetic changes in children with ALL, according to study author Adam de Smith, PhD, of the University of California San Francisco.
“With more smoking among the parents, we saw more deletions within the child’s ALL cells at diagnosis,” Dr de smith said.
For this study, he and his colleagues looked at pre-treatment tumor samples from 559 ALL patients.
The team wanted to see if any of the 8 genes that are frequently deleted in ALL patients (CDKN2A, ETV6, IKZF1, PAX5, RB1, BTG1, PAR1 region, and EBF1) were missing in the samples.
Questionnaires were given to parents to find out if smoking habits impacted the number of genetic deletions. Data was corroborated by a biomarker in newborns’ blood samples that indicates exposure to maternal smoking during pregnancy.
The researchers found that approximately two-thirds of the tumor samples (n=353) contained at least 1 deletion.
Deletions were considerably more common in children whose mothers had smoked during pregnancy and after birth.
For each 5 cigarettes smoked daily during pregnancy, there was a 22% increase in the number of deletions. For each 5 cigarettes smoked daily during breastfeeding, there was a 74% increase in the number of deletions.
Smoking of 5 cigarettes daily by the mother or father before conception was associated with a 7% to 8% higher number of deletions.
Role of child age and sex
One discovery the researchers found intriguing was the link between the fathers’ pre-conception smoking and their child’s age at diagnosis.
“There was a significant effect on deletion numbers in cases where the patient was age 6 or younger,” Dr de Smith said. “Our results suggest that paternal pre-conception smoking, which is known to cause oxidative damage to sperm DNA, may lead to a higher propensity of deletions in children with earlier-onset ALL.”
“It is also true that some of those fathers who smoked before conception also continue to smoke in the presence of the mother and child, so more research is needed to explain the mechanism of smoking-related damage in all of the time periods of exposure to the child.”
In addition, male children were found to be more sensitive to the effects of maternal smoking, including smoking that occurred pre-conception.
The researchers said this could be explained by the fact that male fetuses grow more rapidly, which leads to increased vulnerability of developing lymphocytes to toxins that cause genetic damage.
“Our study indicates that the more tobacco exposure, the more cumulative DNA damage is evident in the ALL cell,” said study author Joseph Wiemels, PhD, of the University of California San Francisco.
“While causes of ALL are multifactorial—including the inborn genetic makeup of the child, patterns of infection, pesticides, and other environmental exposure—if there was no smoking in the environment, then there would likely be fewer children with the disease. We may add ALL to the long list of diseases impacted by smoking, and, in this case, affecting one of our most vulnerable populations—our children.”
Smoking by either parent helps promote genetic deletions in children that are associated with the development and progression of acute lymphoblastic leukemia (ALL), according to a study published in Cancer Research.
The strongest associations in this study were found in children whose parents smoked while the children were in utero and during their infancy.
However, the genetic deletions were also noted in the offspring of parents who may have quit smoking even before conception.
The link between ALL and parental smoking has already been established, but this is the first study that points to specific genetic changes in children with ALL, according to study author Adam de Smith, PhD, of the University of California San Francisco.
“With more smoking among the parents, we saw more deletions within the child’s ALL cells at diagnosis,” Dr de smith said.
For this study, he and his colleagues looked at pre-treatment tumor samples from 559 ALL patients.
The team wanted to see if any of the 8 genes that are frequently deleted in ALL patients (CDKN2A, ETV6, IKZF1, PAX5, RB1, BTG1, PAR1 region, and EBF1) were missing in the samples.
Questionnaires were given to parents to find out if smoking habits impacted the number of genetic deletions. Data was corroborated by a biomarker in newborns’ blood samples that indicates exposure to maternal smoking during pregnancy.
The researchers found that approximately two-thirds of the tumor samples (n=353) contained at least 1 deletion.
Deletions were considerably more common in children whose mothers had smoked during pregnancy and after birth.
For each 5 cigarettes smoked daily during pregnancy, there was a 22% increase in the number of deletions. For each 5 cigarettes smoked daily during breastfeeding, there was a 74% increase in the number of deletions.
Smoking of 5 cigarettes daily by the mother or father before conception was associated with a 7% to 8% higher number of deletions.
Role of child age and sex
One discovery the researchers found intriguing was the link between the fathers’ pre-conception smoking and their child’s age at diagnosis.
“There was a significant effect on deletion numbers in cases where the patient was age 6 or younger,” Dr de Smith said. “Our results suggest that paternal pre-conception smoking, which is known to cause oxidative damage to sperm DNA, may lead to a higher propensity of deletions in children with earlier-onset ALL.”
“It is also true that some of those fathers who smoked before conception also continue to smoke in the presence of the mother and child, so more research is needed to explain the mechanism of smoking-related damage in all of the time periods of exposure to the child.”
In addition, male children were found to be more sensitive to the effects of maternal smoking, including smoking that occurred pre-conception.
The researchers said this could be explained by the fact that male fetuses grow more rapidly, which leads to increased vulnerability of developing lymphocytes to toxins that cause genetic damage.
“Our study indicates that the more tobacco exposure, the more cumulative DNA damage is evident in the ALL cell,” said study author Joseph Wiemels, PhD, of the University of California San Francisco.
“While causes of ALL are multifactorial—including the inborn genetic makeup of the child, patterns of infection, pesticides, and other environmental exposure—if there was no smoking in the environment, then there would likely be fewer children with the disease. We may add ALL to the long list of diseases impacted by smoking, and, in this case, affecting one of our most vulnerable populations—our children.”
Smoking by either parent helps promote genetic deletions in children that are associated with the development and progression of acute lymphoblastic leukemia (ALL), according to a study published in Cancer Research.
The strongest associations in this study were found in children whose parents smoked while the children were in utero and during their infancy.
However, the genetic deletions were also noted in the offspring of parents who may have quit smoking even before conception.
The link between ALL and parental smoking has already been established, but this is the first study that points to specific genetic changes in children with ALL, according to study author Adam de Smith, PhD, of the University of California San Francisco.
“With more smoking among the parents, we saw more deletions within the child’s ALL cells at diagnosis,” Dr de smith said.
For this study, he and his colleagues looked at pre-treatment tumor samples from 559 ALL patients.
The team wanted to see if any of the 8 genes that are frequently deleted in ALL patients (CDKN2A, ETV6, IKZF1, PAX5, RB1, BTG1, PAR1 region, and EBF1) were missing in the samples.
Questionnaires were given to parents to find out if smoking habits impacted the number of genetic deletions. Data was corroborated by a biomarker in newborns’ blood samples that indicates exposure to maternal smoking during pregnancy.
The researchers found that approximately two-thirds of the tumor samples (n=353) contained at least 1 deletion.
Deletions were considerably more common in children whose mothers had smoked during pregnancy and after birth.
For each 5 cigarettes smoked daily during pregnancy, there was a 22% increase in the number of deletions. For each 5 cigarettes smoked daily during breastfeeding, there was a 74% increase in the number of deletions.
Smoking of 5 cigarettes daily by the mother or father before conception was associated with a 7% to 8% higher number of deletions.
Role of child age and sex
One discovery the researchers found intriguing was the link between the fathers’ pre-conception smoking and their child’s age at diagnosis.
“There was a significant effect on deletion numbers in cases where the patient was age 6 or younger,” Dr de Smith said. “Our results suggest that paternal pre-conception smoking, which is known to cause oxidative damage to sperm DNA, may lead to a higher propensity of deletions in children with earlier-onset ALL.”
“It is also true that some of those fathers who smoked before conception also continue to smoke in the presence of the mother and child, so more research is needed to explain the mechanism of smoking-related damage in all of the time periods of exposure to the child.”
In addition, male children were found to be more sensitive to the effects of maternal smoking, including smoking that occurred pre-conception.
The researchers said this could be explained by the fact that male fetuses grow more rapidly, which leads to increased vulnerability of developing lymphocytes to toxins that cause genetic damage.
“Our study indicates that the more tobacco exposure, the more cumulative DNA damage is evident in the ALL cell,” said study author Joseph Wiemels, PhD, of the University of California San Francisco.
“While causes of ALL are multifactorial—including the inborn genetic makeup of the child, patterns of infection, pesticides, and other environmental exposure—if there was no smoking in the environment, then there would likely be fewer children with the disease. We may add ALL to the long list of diseases impacted by smoking, and, in this case, affecting one of our most vulnerable populations—our children.”
How stress controls hemoglobin levels in blood
Researchers say they have discovered a new mechanism through which globin genes are expressed.
Their discovery, described in Cell Research, indicates that cellular stress is needed for the production of hemoglobin.
“Surprisingly, we have revealed an entirely new mechanism through which hemoglobin gene expression is regulated by stress,” said study author Raymond Kaempfer, PhD, of the Hebrew University of Jerusalem in Israel.
“An intracellular signal, essential for coping with stress, is absolutely necessary to allow for hemoglobin production. That stress signal is activated by the hemoglobin gene itself. Although we have long known that this signal strongly inhibits protein synthesis in general, during hemoglobin gene expression, it first plays its indispensable, positive role before being turned off promptly to allow for massive hemoglobin formation needed for breathing.”
To produce a globin protein molecule, the DNA of the globin gene is first transcribed into a long RNA molecule from which internal segments must be spliced out to generate the RNA template for protein synthesis in the red cell.
The researchers found that, for each of the adult and fetal globin genes, the splicing of its RNA is strictly controlled by an intracellular stress signal.
The signal, which has been known for a long time, involves an enzyme called PKR. This enzyme remains silent unless it is activated by a specific RNA structure thought to occur only in RNA made by viruses.
What the researchers discovered is that the long RNAs transcribed from the globin genes each contain a short intrinsic RNA element that is capable of strongly activating PKR.
Unless the PKR enzyme is activated in this manner, the long RNA cannot be spliced to form the mature RNA template for globin protein synthesis.
Once activated, PKR will place a phosphate onto a key initiation factor needed for the synthesis of all proteins, called eIF2-alpha. That, in turn, leads to inactivation of eIF2-alpha, resulting in a block in protein synthesis. This process is essential for coping with stress.
The researchers discovered that, once activated, PKR must phosphorylate eIF2-alpha, and that phosphorylated eIF2-alpha is essential to form the machinery needed to splice globin RNA.
In the splicing process, removal of an internal RNA segment causes the mature RNA product to refold such that it no longer will activate PKR. This allows for unimpeded synthesis on this RNA of the essential globin protein chains at maximal rates, which allows for effective oxygen breathing.
In other words, the ability to activate PKR remains transient, serving solely to enable splicing.
Thus, the researchers have demonstrated a novel, positive role for PKR activation and eIF2-alpha phosphorylation in human globin RNA splicing, in contrast to the long-standing negative role of this intracellular stress response in protein synthesis.
The realization that stress is essential may have implications for how we understand hemoglobin expression.
“What this boils down to is that, even at the cellular level, stress and the ability to mount a stress response are essential to our survival,” Dr Kaempfer said. “We have long known this in relation to other biological processes, and now we see that it is at play even for the tiny molecules that carry oxygen in our blood.”
Researchers say they have discovered a new mechanism through which globin genes are expressed.
Their discovery, described in Cell Research, indicates that cellular stress is needed for the production of hemoglobin.
“Surprisingly, we have revealed an entirely new mechanism through which hemoglobin gene expression is regulated by stress,” said study author Raymond Kaempfer, PhD, of the Hebrew University of Jerusalem in Israel.
“An intracellular signal, essential for coping with stress, is absolutely necessary to allow for hemoglobin production. That stress signal is activated by the hemoglobin gene itself. Although we have long known that this signal strongly inhibits protein synthesis in general, during hemoglobin gene expression, it first plays its indispensable, positive role before being turned off promptly to allow for massive hemoglobin formation needed for breathing.”
To produce a globin protein molecule, the DNA of the globin gene is first transcribed into a long RNA molecule from which internal segments must be spliced out to generate the RNA template for protein synthesis in the red cell.
The researchers found that, for each of the adult and fetal globin genes, the splicing of its RNA is strictly controlled by an intracellular stress signal.
The signal, which has been known for a long time, involves an enzyme called PKR. This enzyme remains silent unless it is activated by a specific RNA structure thought to occur only in RNA made by viruses.
What the researchers discovered is that the long RNAs transcribed from the globin genes each contain a short intrinsic RNA element that is capable of strongly activating PKR.
Unless the PKR enzyme is activated in this manner, the long RNA cannot be spliced to form the mature RNA template for globin protein synthesis.
Once activated, PKR will place a phosphate onto a key initiation factor needed for the synthesis of all proteins, called eIF2-alpha. That, in turn, leads to inactivation of eIF2-alpha, resulting in a block in protein synthesis. This process is essential for coping with stress.
The researchers discovered that, once activated, PKR must phosphorylate eIF2-alpha, and that phosphorylated eIF2-alpha is essential to form the machinery needed to splice globin RNA.
In the splicing process, removal of an internal RNA segment causes the mature RNA product to refold such that it no longer will activate PKR. This allows for unimpeded synthesis on this RNA of the essential globin protein chains at maximal rates, which allows for effective oxygen breathing.
In other words, the ability to activate PKR remains transient, serving solely to enable splicing.
Thus, the researchers have demonstrated a novel, positive role for PKR activation and eIF2-alpha phosphorylation in human globin RNA splicing, in contrast to the long-standing negative role of this intracellular stress response in protein synthesis.
The realization that stress is essential may have implications for how we understand hemoglobin expression.
“What this boils down to is that, even at the cellular level, stress and the ability to mount a stress response are essential to our survival,” Dr Kaempfer said. “We have long known this in relation to other biological processes, and now we see that it is at play even for the tiny molecules that carry oxygen in our blood.”
Researchers say they have discovered a new mechanism through which globin genes are expressed.
Their discovery, described in Cell Research, indicates that cellular stress is needed for the production of hemoglobin.
“Surprisingly, we have revealed an entirely new mechanism through which hemoglobin gene expression is regulated by stress,” said study author Raymond Kaempfer, PhD, of the Hebrew University of Jerusalem in Israel.
“An intracellular signal, essential for coping with stress, is absolutely necessary to allow for hemoglobin production. That stress signal is activated by the hemoglobin gene itself. Although we have long known that this signal strongly inhibits protein synthesis in general, during hemoglobin gene expression, it first plays its indispensable, positive role before being turned off promptly to allow for massive hemoglobin formation needed for breathing.”
To produce a globin protein molecule, the DNA of the globin gene is first transcribed into a long RNA molecule from which internal segments must be spliced out to generate the RNA template for protein synthesis in the red cell.
The researchers found that, for each of the adult and fetal globin genes, the splicing of its RNA is strictly controlled by an intracellular stress signal.
The signal, which has been known for a long time, involves an enzyme called PKR. This enzyme remains silent unless it is activated by a specific RNA structure thought to occur only in RNA made by viruses.
What the researchers discovered is that the long RNAs transcribed from the globin genes each contain a short intrinsic RNA element that is capable of strongly activating PKR.
Unless the PKR enzyme is activated in this manner, the long RNA cannot be spliced to form the mature RNA template for globin protein synthesis.
Once activated, PKR will place a phosphate onto a key initiation factor needed for the synthesis of all proteins, called eIF2-alpha. That, in turn, leads to inactivation of eIF2-alpha, resulting in a block in protein synthesis. This process is essential for coping with stress.
The researchers discovered that, once activated, PKR must phosphorylate eIF2-alpha, and that phosphorylated eIF2-alpha is essential to form the machinery needed to splice globin RNA.
In the splicing process, removal of an internal RNA segment causes the mature RNA product to refold such that it no longer will activate PKR. This allows for unimpeded synthesis on this RNA of the essential globin protein chains at maximal rates, which allows for effective oxygen breathing.
In other words, the ability to activate PKR remains transient, serving solely to enable splicing.
Thus, the researchers have demonstrated a novel, positive role for PKR activation and eIF2-alpha phosphorylation in human globin RNA splicing, in contrast to the long-standing negative role of this intracellular stress response in protein synthesis.
The realization that stress is essential may have implications for how we understand hemoglobin expression.
“What this boils down to is that, even at the cellular level, stress and the ability to mount a stress response are essential to our survival,” Dr Kaempfer said. “We have long known this in relation to other biological processes, and now we see that it is at play even for the tiny molecules that carry oxygen in our blood.”
Disease burden impacts outcome of CAR T-cell therapy in B-ALL
WASHINGTON, DC—Results of a retrospective study suggest pretreatment disease burden impacts the outcome of chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).
Patients who had minimal residual disease (MRD) prior to treatment had superior event-free and overall survival compared to patients who had morphologic disease before treatment.
Patients with MRD were also less likely to experience cytokine release syndrome (CRS) and neurologic toxicity.
Jae Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York, presented these results at the AACR Annual Meeting 2017 (abstract CT078).
This study was funded by Juno Therapeutics, the National Cancer Institute, the Terry Fox Foundation, and MSKCC Experimental Therapeutics Center.
“[W]e and other groups have developed and tested CD19-specific [19-28z] CAR T-cell therapy and have reported encouraging results, with high initial complete response rates in patients with B-ALL,” Dr Park said.
“However, relapses are common, even after achieving seemingly deep remission, and severe toxicities have been observed in some patients.”
To gain more insight into these results, Dr Park and his colleagues retrospectively analyzed data from a prospective clinical trial that tested 19-28z CAR T-cell therapy in patients with B-ALL.
All 51 adults in this trial had relapsed after or were refractory to 1 or more conventional multiagent chemotherapy regimens.
The researchers measured disease burden prior to CAR T-cell infusion in all patients and divided them into 2 cohorts:
- 20 patients who had MRD—less than 5% blasts in the bone marrow
- 31 patients who had morphologic disease—5% or more blasts in the bone marrow.
Response and survival
The complete response rate was 95% in the MRD cohort and 77% in the morphologic disease cohort, a difference that was not statistically significant.
At a median follow-up of 18 months, the median event-free survival and overall survival had not been reached for patients in the MRD cohort (because most were still alive and disease-free).
However, for patients in the morphologic disease cohort, the median event-free survival was 6.3 months (P=0.0005), and the median overall survival was 17 months (P=0.0189).
Role of transplant
The researchers found that long-term survival did not improve for patients who proceeded to hematopoietic stem cell transplant (HSCT), regardless of their disease burden at baseline.
“While more patients and longer follow-up will be needed to adequately address the significance of HSCT, the result of this analysis raises a question as to whether 19-28z CAR therapy can be considered as a definitive, curative therapy rather than a bridge to stem cell transplant, at least in a subset of patients,” Dr Park noted.
“Our data suggest that incorporation of 19-28z CAR T cells at the time of MRD following first-line chemotherapy will maximize the durability of CAR T-cell-mediated remissions and survival and can potentially spare these high-risk patients from HSCT, rather than waiting until they relapse morphologically and then trying CAR T-cell therapy when it is less likely to achieve a durable long-term outcome.”
Adverse events and limitations
Patients from the MRD cohort fared better than the morphologic disease cohort in terms of CRS and neurologic toxicity.
Forty-two percent of patients in the morphologic disease cohort developed CRS, compared to 5% of patients in the MRD cohort (P=0.0326).
Neurologic toxicity occurred in 58% of patients in the morphologic disease cohort and 15% of those in the MRD cohort (P=0.0001).
Dr Park noted that a limitation of this study is its retrospective nature, and the findings will need to be validated prospectively.
Furthermore, the analysis on the impact of allogeneic HSCT was limited by a relatively small sample size in each cohort.
WASHINGTON, DC—Results of a retrospective study suggest pretreatment disease burden impacts the outcome of chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).
Patients who had minimal residual disease (MRD) prior to treatment had superior event-free and overall survival compared to patients who had morphologic disease before treatment.
Patients with MRD were also less likely to experience cytokine release syndrome (CRS) and neurologic toxicity.
Jae Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York, presented these results at the AACR Annual Meeting 2017 (abstract CT078).
This study was funded by Juno Therapeutics, the National Cancer Institute, the Terry Fox Foundation, and MSKCC Experimental Therapeutics Center.
“[W]e and other groups have developed and tested CD19-specific [19-28z] CAR T-cell therapy and have reported encouraging results, with high initial complete response rates in patients with B-ALL,” Dr Park said.
“However, relapses are common, even after achieving seemingly deep remission, and severe toxicities have been observed in some patients.”
To gain more insight into these results, Dr Park and his colleagues retrospectively analyzed data from a prospective clinical trial that tested 19-28z CAR T-cell therapy in patients with B-ALL.
All 51 adults in this trial had relapsed after or were refractory to 1 or more conventional multiagent chemotherapy regimens.
The researchers measured disease burden prior to CAR T-cell infusion in all patients and divided them into 2 cohorts:
- 20 patients who had MRD—less than 5% blasts in the bone marrow
- 31 patients who had morphologic disease—5% or more blasts in the bone marrow.
Response and survival
The complete response rate was 95% in the MRD cohort and 77% in the morphologic disease cohort, a difference that was not statistically significant.
At a median follow-up of 18 months, the median event-free survival and overall survival had not been reached for patients in the MRD cohort (because most were still alive and disease-free).
However, for patients in the morphologic disease cohort, the median event-free survival was 6.3 months (P=0.0005), and the median overall survival was 17 months (P=0.0189).
Role of transplant
The researchers found that long-term survival did not improve for patients who proceeded to hematopoietic stem cell transplant (HSCT), regardless of their disease burden at baseline.
“While more patients and longer follow-up will be needed to adequately address the significance of HSCT, the result of this analysis raises a question as to whether 19-28z CAR therapy can be considered as a definitive, curative therapy rather than a bridge to stem cell transplant, at least in a subset of patients,” Dr Park noted.
“Our data suggest that incorporation of 19-28z CAR T cells at the time of MRD following first-line chemotherapy will maximize the durability of CAR T-cell-mediated remissions and survival and can potentially spare these high-risk patients from HSCT, rather than waiting until they relapse morphologically and then trying CAR T-cell therapy when it is less likely to achieve a durable long-term outcome.”
Adverse events and limitations
Patients from the MRD cohort fared better than the morphologic disease cohort in terms of CRS and neurologic toxicity.
Forty-two percent of patients in the morphologic disease cohort developed CRS, compared to 5% of patients in the MRD cohort (P=0.0326).
Neurologic toxicity occurred in 58% of patients in the morphologic disease cohort and 15% of those in the MRD cohort (P=0.0001).
Dr Park noted that a limitation of this study is its retrospective nature, and the findings will need to be validated prospectively.
Furthermore, the analysis on the impact of allogeneic HSCT was limited by a relatively small sample size in each cohort.
WASHINGTON, DC—Results of a retrospective study suggest pretreatment disease burden impacts the outcome of chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).
Patients who had minimal residual disease (MRD) prior to treatment had superior event-free and overall survival compared to patients who had morphologic disease before treatment.
Patients with MRD were also less likely to experience cytokine release syndrome (CRS) and neurologic toxicity.
Jae Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York, presented these results at the AACR Annual Meeting 2017 (abstract CT078).
This study was funded by Juno Therapeutics, the National Cancer Institute, the Terry Fox Foundation, and MSKCC Experimental Therapeutics Center.
“[W]e and other groups have developed and tested CD19-specific [19-28z] CAR T-cell therapy and have reported encouraging results, with high initial complete response rates in patients with B-ALL,” Dr Park said.
“However, relapses are common, even after achieving seemingly deep remission, and severe toxicities have been observed in some patients.”
To gain more insight into these results, Dr Park and his colleagues retrospectively analyzed data from a prospective clinical trial that tested 19-28z CAR T-cell therapy in patients with B-ALL.
All 51 adults in this trial had relapsed after or were refractory to 1 or more conventional multiagent chemotherapy regimens.
The researchers measured disease burden prior to CAR T-cell infusion in all patients and divided them into 2 cohorts:
- 20 patients who had MRD—less than 5% blasts in the bone marrow
- 31 patients who had morphologic disease—5% or more blasts in the bone marrow.
Response and survival
The complete response rate was 95% in the MRD cohort and 77% in the morphologic disease cohort, a difference that was not statistically significant.
At a median follow-up of 18 months, the median event-free survival and overall survival had not been reached for patients in the MRD cohort (because most were still alive and disease-free).
However, for patients in the morphologic disease cohort, the median event-free survival was 6.3 months (P=0.0005), and the median overall survival was 17 months (P=0.0189).
Role of transplant
The researchers found that long-term survival did not improve for patients who proceeded to hematopoietic stem cell transplant (HSCT), regardless of their disease burden at baseline.
“While more patients and longer follow-up will be needed to adequately address the significance of HSCT, the result of this analysis raises a question as to whether 19-28z CAR therapy can be considered as a definitive, curative therapy rather than a bridge to stem cell transplant, at least in a subset of patients,” Dr Park noted.
“Our data suggest that incorporation of 19-28z CAR T cells at the time of MRD following first-line chemotherapy will maximize the durability of CAR T-cell-mediated remissions and survival and can potentially spare these high-risk patients from HSCT, rather than waiting until they relapse morphologically and then trying CAR T-cell therapy when it is less likely to achieve a durable long-term outcome.”
Adverse events and limitations
Patients from the MRD cohort fared better than the morphologic disease cohort in terms of CRS and neurologic toxicity.
Forty-two percent of patients in the morphologic disease cohort developed CRS, compared to 5% of patients in the MRD cohort (P=0.0326).
Neurologic toxicity occurred in 58% of patients in the morphologic disease cohort and 15% of those in the MRD cohort (P=0.0001).
Dr Park noted that a limitation of this study is its retrospective nature, and the findings will need to be validated prospectively.
Furthermore, the analysis on the impact of allogeneic HSCT was limited by a relatively small sample size in each cohort.
FDA clears direct-to-consumer marketing of genetic risk tests
The US Food and Drug Administration (FDA) has authorized marketing of 23andMe Personal Genome Service (PGS) Genetic Health Risk (GHR) tests for 10 medical conditions.
These are the first direct-to-consumer tests authorized by the FDA that provide information on an individual’s genetic predisposition to certain conditions, including factor XI deficiency, glucose-6-phosphate dehydrogenase (G6PD) deficiency, hereditary hemochromatosis, hereditary thrombophilia, and other conditions.
The GHR tests work by isolating DNA from a saliva sample, which is then tested for more than 500,000 genetic variants.
Consumers receive reports of the results, which tell them if they have an increased risk of developing any of the following 10 conditions.
Factor XI deficiency
The 23andMe PGS Genetic Health Risk Report for Factor XI Deficiency is indicated for reporting of the F283L, E117X, and IVS14+1G>A variants in the F11 gene.
This report describes if a person has a variant associated with factor XI deficiency and the potential for a higher risk of excessive bleeding following trauma or surgery, but it does not describe a person’s overall risk for excessive bleeding. This report is most relevant for people of Ashkenazi Jewish descent.
G6PD deficiency
The 23andMe PGS Genetic Health Risk Report for Glucose-6-Phosphate-Dehydrogenase Deficiency is indicated for reporting of the Val68Met variant in the G6PD gene.
This report describes if a person has a variant associated with G6PD deficiency and a higher risk for episodes of anemia, but it does not describe a person’s overall risk of developing anemia. This report is most relevant for people of African descent.
Hereditary hemochromatosis
The 23andMe PGS Genetic Health Risk Report for Hereditary Hemochromatosis is indicated for reporting of the C282Y and H63D variants in the HFE gene.
This report describes if a person has variants associated with hereditary hemochromatosis and a higher risk for iron overload, but it does not describe a person’s overall risk of developing iron overload. This report is most relevant for people of European descent.
Hereditary thrombophilia
The 23andMe PGS Genetic Health Risk Report for Hereditary Thrombophilia is indicated for reporting of the factor V Leiden variant in the F5 gene, as well as the prothrombin G20210A variant in the F2 gene.
This report describes if a person has variants associated with a higher risk of thrombosis, but it does not describe a person’s overall risk of developing thrombosis. This report is most relevant for people of European descent.
Alpha-1 antitrypsin deficiency (AATD)
The 23andMe PGS Genetic Health Risk Report for Alpha-I Antitrypsin Deficiency is indicated for reporting of the PI*Z and PI*S variants in the SERPINA1 gene.
This report describes if a person has variants associated with AATD and a higher risk for lung or liver disease, but it does not describe a person’s overall risk of developing lung or liver disease. This report is most relevant for people of European descent.
Celiac disease
The 23andMe PGS Genetic Health Risk Report for Celiac Disease is indicated for reporting of a variant in the HLA-DQ2.5 haplotype.
The report describes if a person has a haplotype associated with an increased risk of developing celiac disease, but it does not describe a person’s overall risk for developing celiac disease. This report is most relevant for people of European descent.
Early onset primary dystonia (DYT1/TOR1A-related)
The 23andMe PGS Genetic Health Risk Report for Early-Onset Primary Dystonia (DYT1/TOR1A-Related) is indicated for reporting of the deltaE302/303 variant in the DYT1 gene.
This report describes if a person has variants associated with a higher risk for early-onset primary dystonia, but it does not describe a person’s overall risk of developing dystonia. This report is most relevant for people of Ashkenazi Jewish descent.
Gaucher disease
The 23andMe PGS Genetic Health Risk Report for Gaucher Disease Type 1 is indicated for reporting of the N370S, 84GG, and V394L variants in the GBA gene.
This report describes if a person has variants associated with an increased risk for developing carrier status for Gaucher disease type 1 in adults. This report also describes if a result is associated with personal risk for developing symptoms of Gaucher disease type 1, but it does not describe a person’s overall risk of developing Gaucher disease type 1.
This test is most relevant for people of Ashkenazi Jewish descent.
Late-onset Alzheimer’s disease
The 23andMe PGS Genetic Health Risk Report for Late-onset Alzheimer’s Disease is indicated for reporting of the ε4 variant in the APOE gene.
The report describes if a person’s genetic result is associated with an increased risk of developing late-onset Alzheimer’s disease, but it does not describe a person’s overall risk of developing Alzheimer’s disease.
The ε4 variant included in this report is found and has been studied in many ethnicities. Detailed risk estimates have been studied the most in people of European descent.
Parkinson’s disease
The 23andMe PGS Genetic Health Risk Report for Parkinson’s Disease is indicated for reporting of the G2019S variant in the LRRK2 gene and the N370S variant in the GBA gene.
The report describes if a person’s genetic result is associated with an increased risk of developing Parkinson’s disease, but it does not describe a person’s overall risk of developing Parkinson’s disease. The test is most relevant for people of European, Ashkenazi Jewish, and North African Berber descent.
Access to testing
23andMe, Inc. said it will release its first set of GHR tests—for hereditary thrombophilia, late-onset Alzheimer’s disease, Parkinson’s disease, alpha-1 antitrypsin deficiency, and Gaucher disease—this month. The remaining tests will follow.
New 23andMe Health + Ancestry Service customers in the US will have access to these tests. Current 23andMe customers will be notified directly regarding their eligibility.
About the marketing authorization
The FDA reviewed data for the 23andMe GHR tests through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.
Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the tests’ accuracy, reliability, and clinical relevance. These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for these and similar GHR tests.
The FDA intends to exempt additional 23andMe GHR tests from premarket review, and GHR tests from other makers may be exempt after submitting their first premarket notification. A proposed exemption of this kind would allow other, similar tests to enter the market as quickly as possible after a one-time FDA review.
Excluded from the current marketing authorization and any future, related exemption are GHR tests that function as diagnostic tests.
The US Food and Drug Administration (FDA) has authorized marketing of 23andMe Personal Genome Service (PGS) Genetic Health Risk (GHR) tests for 10 medical conditions.
These are the first direct-to-consumer tests authorized by the FDA that provide information on an individual’s genetic predisposition to certain conditions, including factor XI deficiency, glucose-6-phosphate dehydrogenase (G6PD) deficiency, hereditary hemochromatosis, hereditary thrombophilia, and other conditions.
The GHR tests work by isolating DNA from a saliva sample, which is then tested for more than 500,000 genetic variants.
Consumers receive reports of the results, which tell them if they have an increased risk of developing any of the following 10 conditions.
Factor XI deficiency
The 23andMe PGS Genetic Health Risk Report for Factor XI Deficiency is indicated for reporting of the F283L, E117X, and IVS14+1G>A variants in the F11 gene.
This report describes if a person has a variant associated with factor XI deficiency and the potential for a higher risk of excessive bleeding following trauma or surgery, but it does not describe a person’s overall risk for excessive bleeding. This report is most relevant for people of Ashkenazi Jewish descent.
G6PD deficiency
The 23andMe PGS Genetic Health Risk Report for Glucose-6-Phosphate-Dehydrogenase Deficiency is indicated for reporting of the Val68Met variant in the G6PD gene.
This report describes if a person has a variant associated with G6PD deficiency and a higher risk for episodes of anemia, but it does not describe a person’s overall risk of developing anemia. This report is most relevant for people of African descent.
Hereditary hemochromatosis
The 23andMe PGS Genetic Health Risk Report for Hereditary Hemochromatosis is indicated for reporting of the C282Y and H63D variants in the HFE gene.
This report describes if a person has variants associated with hereditary hemochromatosis and a higher risk for iron overload, but it does not describe a person’s overall risk of developing iron overload. This report is most relevant for people of European descent.
Hereditary thrombophilia
The 23andMe PGS Genetic Health Risk Report for Hereditary Thrombophilia is indicated for reporting of the factor V Leiden variant in the F5 gene, as well as the prothrombin G20210A variant in the F2 gene.
This report describes if a person has variants associated with a higher risk of thrombosis, but it does not describe a person’s overall risk of developing thrombosis. This report is most relevant for people of European descent.
Alpha-1 antitrypsin deficiency (AATD)
The 23andMe PGS Genetic Health Risk Report for Alpha-I Antitrypsin Deficiency is indicated for reporting of the PI*Z and PI*S variants in the SERPINA1 gene.
This report describes if a person has variants associated with AATD and a higher risk for lung or liver disease, but it does not describe a person’s overall risk of developing lung or liver disease. This report is most relevant for people of European descent.
Celiac disease
The 23andMe PGS Genetic Health Risk Report for Celiac Disease is indicated for reporting of a variant in the HLA-DQ2.5 haplotype.
The report describes if a person has a haplotype associated with an increased risk of developing celiac disease, but it does not describe a person’s overall risk for developing celiac disease. This report is most relevant for people of European descent.
Early onset primary dystonia (DYT1/TOR1A-related)
The 23andMe PGS Genetic Health Risk Report for Early-Onset Primary Dystonia (DYT1/TOR1A-Related) is indicated for reporting of the deltaE302/303 variant in the DYT1 gene.
This report describes if a person has variants associated with a higher risk for early-onset primary dystonia, but it does not describe a person’s overall risk of developing dystonia. This report is most relevant for people of Ashkenazi Jewish descent.
Gaucher disease
The 23andMe PGS Genetic Health Risk Report for Gaucher Disease Type 1 is indicated for reporting of the N370S, 84GG, and V394L variants in the GBA gene.
This report describes if a person has variants associated with an increased risk for developing carrier status for Gaucher disease type 1 in adults. This report also describes if a result is associated with personal risk for developing symptoms of Gaucher disease type 1, but it does not describe a person’s overall risk of developing Gaucher disease type 1.
This test is most relevant for people of Ashkenazi Jewish descent.
Late-onset Alzheimer’s disease
The 23andMe PGS Genetic Health Risk Report for Late-onset Alzheimer’s Disease is indicated for reporting of the ε4 variant in the APOE gene.
The report describes if a person’s genetic result is associated with an increased risk of developing late-onset Alzheimer’s disease, but it does not describe a person’s overall risk of developing Alzheimer’s disease.
The ε4 variant included in this report is found and has been studied in many ethnicities. Detailed risk estimates have been studied the most in people of European descent.
Parkinson’s disease
The 23andMe PGS Genetic Health Risk Report for Parkinson’s Disease is indicated for reporting of the G2019S variant in the LRRK2 gene and the N370S variant in the GBA gene.
The report describes if a person’s genetic result is associated with an increased risk of developing Parkinson’s disease, but it does not describe a person’s overall risk of developing Parkinson’s disease. The test is most relevant for people of European, Ashkenazi Jewish, and North African Berber descent.
Access to testing
23andMe, Inc. said it will release its first set of GHR tests—for hereditary thrombophilia, late-onset Alzheimer’s disease, Parkinson’s disease, alpha-1 antitrypsin deficiency, and Gaucher disease—this month. The remaining tests will follow.
New 23andMe Health + Ancestry Service customers in the US will have access to these tests. Current 23andMe customers will be notified directly regarding their eligibility.
About the marketing authorization
The FDA reviewed data for the 23andMe GHR tests through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.
Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the tests’ accuracy, reliability, and clinical relevance. These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for these and similar GHR tests.
The FDA intends to exempt additional 23andMe GHR tests from premarket review, and GHR tests from other makers may be exempt after submitting their first premarket notification. A proposed exemption of this kind would allow other, similar tests to enter the market as quickly as possible after a one-time FDA review.
Excluded from the current marketing authorization and any future, related exemption are GHR tests that function as diagnostic tests.
The US Food and Drug Administration (FDA) has authorized marketing of 23andMe Personal Genome Service (PGS) Genetic Health Risk (GHR) tests for 10 medical conditions.
These are the first direct-to-consumer tests authorized by the FDA that provide information on an individual’s genetic predisposition to certain conditions, including factor XI deficiency, glucose-6-phosphate dehydrogenase (G6PD) deficiency, hereditary hemochromatosis, hereditary thrombophilia, and other conditions.
The GHR tests work by isolating DNA from a saliva sample, which is then tested for more than 500,000 genetic variants.
Consumers receive reports of the results, which tell them if they have an increased risk of developing any of the following 10 conditions.
Factor XI deficiency
The 23andMe PGS Genetic Health Risk Report for Factor XI Deficiency is indicated for reporting of the F283L, E117X, and IVS14+1G>A variants in the F11 gene.
This report describes if a person has a variant associated with factor XI deficiency and the potential for a higher risk of excessive bleeding following trauma or surgery, but it does not describe a person’s overall risk for excessive bleeding. This report is most relevant for people of Ashkenazi Jewish descent.
G6PD deficiency
The 23andMe PGS Genetic Health Risk Report for Glucose-6-Phosphate-Dehydrogenase Deficiency is indicated for reporting of the Val68Met variant in the G6PD gene.
This report describes if a person has a variant associated with G6PD deficiency and a higher risk for episodes of anemia, but it does not describe a person’s overall risk of developing anemia. This report is most relevant for people of African descent.
Hereditary hemochromatosis
The 23andMe PGS Genetic Health Risk Report for Hereditary Hemochromatosis is indicated for reporting of the C282Y and H63D variants in the HFE gene.
This report describes if a person has variants associated with hereditary hemochromatosis and a higher risk for iron overload, but it does not describe a person’s overall risk of developing iron overload. This report is most relevant for people of European descent.
Hereditary thrombophilia
The 23andMe PGS Genetic Health Risk Report for Hereditary Thrombophilia is indicated for reporting of the factor V Leiden variant in the F5 gene, as well as the prothrombin G20210A variant in the F2 gene.
This report describes if a person has variants associated with a higher risk of thrombosis, but it does not describe a person’s overall risk of developing thrombosis. This report is most relevant for people of European descent.
Alpha-1 antitrypsin deficiency (AATD)
The 23andMe PGS Genetic Health Risk Report for Alpha-I Antitrypsin Deficiency is indicated for reporting of the PI*Z and PI*S variants in the SERPINA1 gene.
This report describes if a person has variants associated with AATD and a higher risk for lung or liver disease, but it does not describe a person’s overall risk of developing lung or liver disease. This report is most relevant for people of European descent.
Celiac disease
The 23andMe PGS Genetic Health Risk Report for Celiac Disease is indicated for reporting of a variant in the HLA-DQ2.5 haplotype.
The report describes if a person has a haplotype associated with an increased risk of developing celiac disease, but it does not describe a person’s overall risk for developing celiac disease. This report is most relevant for people of European descent.
Early onset primary dystonia (DYT1/TOR1A-related)
The 23andMe PGS Genetic Health Risk Report for Early-Onset Primary Dystonia (DYT1/TOR1A-Related) is indicated for reporting of the deltaE302/303 variant in the DYT1 gene.
This report describes if a person has variants associated with a higher risk for early-onset primary dystonia, but it does not describe a person’s overall risk of developing dystonia. This report is most relevant for people of Ashkenazi Jewish descent.
Gaucher disease
The 23andMe PGS Genetic Health Risk Report for Gaucher Disease Type 1 is indicated for reporting of the N370S, 84GG, and V394L variants in the GBA gene.
This report describes if a person has variants associated with an increased risk for developing carrier status for Gaucher disease type 1 in adults. This report also describes if a result is associated with personal risk for developing symptoms of Gaucher disease type 1, but it does not describe a person’s overall risk of developing Gaucher disease type 1.
This test is most relevant for people of Ashkenazi Jewish descent.
Late-onset Alzheimer’s disease
The 23andMe PGS Genetic Health Risk Report for Late-onset Alzheimer’s Disease is indicated for reporting of the ε4 variant in the APOE gene.
The report describes if a person’s genetic result is associated with an increased risk of developing late-onset Alzheimer’s disease, but it does not describe a person’s overall risk of developing Alzheimer’s disease.
The ε4 variant included in this report is found and has been studied in many ethnicities. Detailed risk estimates have been studied the most in people of European descent.
Parkinson’s disease
The 23andMe PGS Genetic Health Risk Report for Parkinson’s Disease is indicated for reporting of the G2019S variant in the LRRK2 gene and the N370S variant in the GBA gene.
The report describes if a person’s genetic result is associated with an increased risk of developing Parkinson’s disease, but it does not describe a person’s overall risk of developing Parkinson’s disease. The test is most relevant for people of European, Ashkenazi Jewish, and North African Berber descent.
Access to testing
23andMe, Inc. said it will release its first set of GHR tests—for hereditary thrombophilia, late-onset Alzheimer’s disease, Parkinson’s disease, alpha-1 antitrypsin deficiency, and Gaucher disease—this month. The remaining tests will follow.
New 23andMe Health + Ancestry Service customers in the US will have access to these tests. Current 23andMe customers will be notified directly regarding their eligibility.
About the marketing authorization
The FDA reviewed data for the 23andMe GHR tests through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.
Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the tests’ accuracy, reliability, and clinical relevance. These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for these and similar GHR tests.
The FDA intends to exempt additional 23andMe GHR tests from premarket review, and GHR tests from other makers may be exempt after submitting their first premarket notification. A proposed exemption of this kind would allow other, similar tests to enter the market as quickly as possible after a one-time FDA review.
Excluded from the current marketing authorization and any future, related exemption are GHR tests that function as diagnostic tests.
EC publishes guides on patient blood management
The European Commission (EC) has published guides intended to help hospitals and national authorities implement patient blood management (PBM) programs throughout the European Union.
The EC said its guide for hospitals is intended to help them implement PBM in a practical way, building on already recognized best practices.
The guide is the result of the combined expertise of clinicians and PBM professionals and the experience gathered from a 30-month pilot program implementing PBM in 5 European teaching hospitals.
The EC said this guide is relevant for all medical professionals and organizations involved in caring for patients suffering from anemia, blood loss, and medical conditions that might require transfusion.
The EC’s other PBM guide is intended for national authorities. It lists 10 “essential public health operations,” which encompass a range of activities authorities can engage in to aid the implementation of PBM in their health systems.
The essential public health operations (and examples of activities) are:
- Surveillance—eg, continuously collect patient-level data on anemia, transfusion, and outcomes to measure and guide the implementation of PBM as a standard of care
- Monitoring—eg, recommend the monitoring and flagging of too liberal blood component utilization to prevent health hazards
- Health protection—eg, develop information and education materials for clinicians, quality and safety managers, and hospital administrators
- Health promotion—eg, promote awareness of iron deficiency and iron deficiency anemia
- Disease prevention—eg, create a sense of urgency for PBM as a new evidence-based standard of care through professional training and education
- Governance—eg, create and institute a national PBM steering committee under the authority of the Ministry of Health
- Workforce, equipment, and facilities—eg, provide hospital facilities for PBM
- Organization and funding—eg, organize reallocation of funds and resources toward PBM
- Communication—eg, provide PBM webpage sections for patients, health professionals, and health administrators
- Research—eg, conduct PBM-related studies focusing on patient outcomes, cost-effectiveness, etc.
The EC said the publication of their PBM guides is timely, as the journal Transfusion recently published results from a 5-year PBM program in Western Australia, which is the world’s largest PBM program to date. The program included 605,046 patients admitted to 4 major adult tertiary-care hospitals.
The use of blood products was reduced by 41% during the study period. The program also resulted in a 28% reduction in hospital mortality, a 15% reduction in the average hospital length of stay, a 21% decrease in hospital-acquired infections, and a 31% decrease in the incidence of heart attack or stroke.
The European Commission (EC) has published guides intended to help hospitals and national authorities implement patient blood management (PBM) programs throughout the European Union.
The EC said its guide for hospitals is intended to help them implement PBM in a practical way, building on already recognized best practices.
The guide is the result of the combined expertise of clinicians and PBM professionals and the experience gathered from a 30-month pilot program implementing PBM in 5 European teaching hospitals.
The EC said this guide is relevant for all medical professionals and organizations involved in caring for patients suffering from anemia, blood loss, and medical conditions that might require transfusion.
The EC’s other PBM guide is intended for national authorities. It lists 10 “essential public health operations,” which encompass a range of activities authorities can engage in to aid the implementation of PBM in their health systems.
The essential public health operations (and examples of activities) are:
- Surveillance—eg, continuously collect patient-level data on anemia, transfusion, and outcomes to measure and guide the implementation of PBM as a standard of care
- Monitoring—eg, recommend the monitoring and flagging of too liberal blood component utilization to prevent health hazards
- Health protection—eg, develop information and education materials for clinicians, quality and safety managers, and hospital administrators
- Health promotion—eg, promote awareness of iron deficiency and iron deficiency anemia
- Disease prevention—eg, create a sense of urgency for PBM as a new evidence-based standard of care through professional training and education
- Governance—eg, create and institute a national PBM steering committee under the authority of the Ministry of Health
- Workforce, equipment, and facilities—eg, provide hospital facilities for PBM
- Organization and funding—eg, organize reallocation of funds and resources toward PBM
- Communication—eg, provide PBM webpage sections for patients, health professionals, and health administrators
- Research—eg, conduct PBM-related studies focusing on patient outcomes, cost-effectiveness, etc.
The EC said the publication of their PBM guides is timely, as the journal Transfusion recently published results from a 5-year PBM program in Western Australia, which is the world’s largest PBM program to date. The program included 605,046 patients admitted to 4 major adult tertiary-care hospitals.
The use of blood products was reduced by 41% during the study period. The program also resulted in a 28% reduction in hospital mortality, a 15% reduction in the average hospital length of stay, a 21% decrease in hospital-acquired infections, and a 31% decrease in the incidence of heart attack or stroke.
The European Commission (EC) has published guides intended to help hospitals and national authorities implement patient blood management (PBM) programs throughout the European Union.
The EC said its guide for hospitals is intended to help them implement PBM in a practical way, building on already recognized best practices.
The guide is the result of the combined expertise of clinicians and PBM professionals and the experience gathered from a 30-month pilot program implementing PBM in 5 European teaching hospitals.
The EC said this guide is relevant for all medical professionals and organizations involved in caring for patients suffering from anemia, blood loss, and medical conditions that might require transfusion.
The EC’s other PBM guide is intended for national authorities. It lists 10 “essential public health operations,” which encompass a range of activities authorities can engage in to aid the implementation of PBM in their health systems.
The essential public health operations (and examples of activities) are:
- Surveillance—eg, continuously collect patient-level data on anemia, transfusion, and outcomes to measure and guide the implementation of PBM as a standard of care
- Monitoring—eg, recommend the monitoring and flagging of too liberal blood component utilization to prevent health hazards
- Health protection—eg, develop information and education materials for clinicians, quality and safety managers, and hospital administrators
- Health promotion—eg, promote awareness of iron deficiency and iron deficiency anemia
- Disease prevention—eg, create a sense of urgency for PBM as a new evidence-based standard of care through professional training and education
- Governance—eg, create and institute a national PBM steering committee under the authority of the Ministry of Health
- Workforce, equipment, and facilities—eg, provide hospital facilities for PBM
- Organization and funding—eg, organize reallocation of funds and resources toward PBM
- Communication—eg, provide PBM webpage sections for patients, health professionals, and health administrators
- Research—eg, conduct PBM-related studies focusing on patient outcomes, cost-effectiveness, etc.
The EC said the publication of their PBM guides is timely, as the journal Transfusion recently published results from a 5-year PBM program in Western Australia, which is the world’s largest PBM program to date. The program included 605,046 patients admitted to 4 major adult tertiary-care hospitals.
The use of blood products was reduced by 41% during the study period. The program also resulted in a 28% reduction in hospital mortality, a 15% reduction in the average hospital length of stay, a 21% decrease in hospital-acquired infections, and a 31% decrease in the incidence of heart attack or stroke.
Drug may be new option for difficult-to-treat DLBCL, doc says
WASHINGTON, DC—Selinexor has demonstrated the potential to become a new oral treatment option for patients with difficult-to-treat diffuse large B-cell lymphoma (DLBCL), according to a presenter at the AACR Annual Meeting 2017.
Interim results from the phase 2b SADAL study showed that selinexor produced a 28.6% overall response rate (ORR), with an 11.1% complete response (CR) rate, in a heavily pretreated, older DLBCL population.
Responses were observed in GCB and non-GCB subtypes, and the median duration of response exceeded 7 months.
The most common adverse events (AEs) were fatigue, thrombocytopenia, nausea, anorexia, and vomiting.
Marie Maerevoet, MD, of the Institute Jules Bordet in Brussels, Belgium, presented data from the SADAL study as abstract CT132/13.*
The trial is sponsored by Karyopharm Therapeutics, the company developing selinexor.
Patients and treatment
The study enrolled 72 patients with relapsed or refractory DLBCL. At least 14 weeks had elapsed since their most recent systemic anti-DLBCL therapy.
The patients received selinexor—an oral selective inhibitor of nuclear export (SINE™) compound—at 60 mg or 100 mg twice weekly (days 1 and 3 each week) of each 28-day cycle.
60 mg arm
There were 37 patients in the 60 mg arm. Their median age was 71 (range, 38-87), and most (n=24) were male. Forty-nine percent of these patients (n=18) had GCB DLBCL.
Fourteen percent of patients had high-risk disease (according to the revised international prognostic index). Forty-three percent had high-intermediate-risk, 30% had low-intermediate-risk, and 14% had low-risk disease.
The patients had received a median of 3 prior treatment regimens (range, 2-5). Twenty-seven percent had received a prior transplant.
100 mg arm
There were 35 patients in the 100 mg arm. Their median age was 68 (range, 32-82), and most (n=23) were male. Fifty-one percent of patients (n=18) had GCB DLBCL.
Eleven percent of patients had high-risk, 40% had high-intermediate-risk, 37% had low-intermediate-risk, and 6% had low-risk disease. For 6% of patients, their risk group was unknown.
The patients had received a median of 3 prior treatment regimens (range, 2-5). Forty-six percent had received a prior transplant.
Safety
All 72 patients were evaluable for safety. The most common AEs across both dosing groups were fatigue (65%), thrombocytopenia (54%), nausea (51%), anorexia (49%), vomiting (35%), and anemia (32%).
These events were primarily grades 1 and 2 and were managed with dose modifications and/or standard supportive care.
The 60 mg dose was better tolerated than the 100 mg dose, with fewer dose interruptions and modifications required in the 60 mg arm.
Grade 3/4 AEs that were more common in the 100 mg arm than the 60 mg arm were fatigue (26% vs 11%), thrombocytopenia (46% vs 32%), and anorexia (11% vs 3%).
Efficacy
Sixty-three patients were analyzed for response. The ORR was 28.6% (18/63), with a CR rate of 11.1% (n=7) and a partial response (PR) rate of 17.5% (n=11).
The rate of stable disease (SD) was 14.3% (n=9), and the rate of progressive disease (PD) was 46% (n=29). Seven patients (11.1%) were not evaluable (NE).
The best responses as of March 1, 2017, according to subtype and selinexor dose, were as follows:
| Category | N | ORR | CR | PR | SD | PD | NE |
| 60 mg | 32 | 9 (28.1%) | 4 (12.5%) | 5 (15.6%) | 3 (9.4%) | 17 (53.1%) | 3 (9.4%) |
| 100 mg | 31 | 9 (29.0%) | 3 (9.7%) | 6 (19.4%) | 6 (19.4%) | 12 (38.7%) | 4 (12.9%) |
| GCB subtype | 32 | 8 (25.0%) | 3 (9.4%) | 5 (15.6%) | 6 (18.8%) | 13 (40.6%) | 5 (15.6%) |
| Non-GCB subtype | 31 | 10 (32.3%) | 4 (12.9%) | 6 (19.4%) | 3 (9.7%) | 16 (51.6%) | 2 (6.5%) |
The median duration of response was greater than 7 months. The median time to response was 2 months.
Among responders, the median time on treatment was 9 months, with a median follow-up of 13 months. As of the data cutoff date, 9 responders remained on treatment, including 6 patients with a CR.
The median overall survival was 8 months for all patients. As of the cutoff date, the median survival for the responders had not been reached.
“With the impressive and durable responses observed to date, including in both the GCB and non-GCB subtypes of DLBCL, single-agent selinexor is demonstrating the potential to become a new oral option for this difficult-to-treat patient population who are not candidates for transplantation and whose disease is unlikely to respond to further chemotherapy or targeted agents,” Dr Maerevoet said.
Trial update
As a result of the interim data from SADAL, and in consultation with the US Food and Drug Administration (FDA), Karyopharm is amending the study protocol.
SADAL will become a single-arm study focusing solely on single-agent selinexor dosed at 60 mg twice weekly.
The study is also being amended to reduce the 14-week treatment-free period to 8 weeks in patients who achieved at least a PR on their most recent therapy. Patients who were refractory to or did not achieve at least a PR on their prior therapy will continue with the 14-week treatment-free period.
Karyopharm plans to enroll up to an additional 90 patients to the new 60 mg single-arm cohort and expects to report top-line results from the SADAL study in mid-2018.
The FDA recently lifted a partial clinical hold placed on the SADAL trial and other trials of selinexor.
The FDA had placed the hold due to a lack of information in the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.
*Data in the abstract differ from the presentation.
WASHINGTON, DC—Selinexor has demonstrated the potential to become a new oral treatment option for patients with difficult-to-treat diffuse large B-cell lymphoma (DLBCL), according to a presenter at the AACR Annual Meeting 2017.
Interim results from the phase 2b SADAL study showed that selinexor produced a 28.6% overall response rate (ORR), with an 11.1% complete response (CR) rate, in a heavily pretreated, older DLBCL population.
Responses were observed in GCB and non-GCB subtypes, and the median duration of response exceeded 7 months.
The most common adverse events (AEs) were fatigue, thrombocytopenia, nausea, anorexia, and vomiting.
Marie Maerevoet, MD, of the Institute Jules Bordet in Brussels, Belgium, presented data from the SADAL study as abstract CT132/13.*
The trial is sponsored by Karyopharm Therapeutics, the company developing selinexor.
Patients and treatment
The study enrolled 72 patients with relapsed or refractory DLBCL. At least 14 weeks had elapsed since their most recent systemic anti-DLBCL therapy.
The patients received selinexor—an oral selective inhibitor of nuclear export (SINE™) compound—at 60 mg or 100 mg twice weekly (days 1 and 3 each week) of each 28-day cycle.
60 mg arm
There were 37 patients in the 60 mg arm. Their median age was 71 (range, 38-87), and most (n=24) were male. Forty-nine percent of these patients (n=18) had GCB DLBCL.
Fourteen percent of patients had high-risk disease (according to the revised international prognostic index). Forty-three percent had high-intermediate-risk, 30% had low-intermediate-risk, and 14% had low-risk disease.
The patients had received a median of 3 prior treatment regimens (range, 2-5). Twenty-seven percent had received a prior transplant.
100 mg arm
There were 35 patients in the 100 mg arm. Their median age was 68 (range, 32-82), and most (n=23) were male. Fifty-one percent of patients (n=18) had GCB DLBCL.
Eleven percent of patients had high-risk, 40% had high-intermediate-risk, 37% had low-intermediate-risk, and 6% had low-risk disease. For 6% of patients, their risk group was unknown.
The patients had received a median of 3 prior treatment regimens (range, 2-5). Forty-six percent had received a prior transplant.
Safety
All 72 patients were evaluable for safety. The most common AEs across both dosing groups were fatigue (65%), thrombocytopenia (54%), nausea (51%), anorexia (49%), vomiting (35%), and anemia (32%).
These events were primarily grades 1 and 2 and were managed with dose modifications and/or standard supportive care.
The 60 mg dose was better tolerated than the 100 mg dose, with fewer dose interruptions and modifications required in the 60 mg arm.
Grade 3/4 AEs that were more common in the 100 mg arm than the 60 mg arm were fatigue (26% vs 11%), thrombocytopenia (46% vs 32%), and anorexia (11% vs 3%).
Efficacy
Sixty-three patients were analyzed for response. The ORR was 28.6% (18/63), with a CR rate of 11.1% (n=7) and a partial response (PR) rate of 17.5% (n=11).
The rate of stable disease (SD) was 14.3% (n=9), and the rate of progressive disease (PD) was 46% (n=29). Seven patients (11.1%) were not evaluable (NE).
The best responses as of March 1, 2017, according to subtype and selinexor dose, were as follows:
| Category | N | ORR | CR | PR | SD | PD | NE |
| 60 mg | 32 | 9 (28.1%) | 4 (12.5%) | 5 (15.6%) | 3 (9.4%) | 17 (53.1%) | 3 (9.4%) |
| 100 mg | 31 | 9 (29.0%) | 3 (9.7%) | 6 (19.4%) | 6 (19.4%) | 12 (38.7%) | 4 (12.9%) |
| GCB subtype | 32 | 8 (25.0%) | 3 (9.4%) | 5 (15.6%) | 6 (18.8%) | 13 (40.6%) | 5 (15.6%) |
| Non-GCB subtype | 31 | 10 (32.3%) | 4 (12.9%) | 6 (19.4%) | 3 (9.7%) | 16 (51.6%) | 2 (6.5%) |
The median duration of response was greater than 7 months. The median time to response was 2 months.
Among responders, the median time on treatment was 9 months, with a median follow-up of 13 months. As of the data cutoff date, 9 responders remained on treatment, including 6 patients with a CR.
The median overall survival was 8 months for all patients. As of the cutoff date, the median survival for the responders had not been reached.
“With the impressive and durable responses observed to date, including in both the GCB and non-GCB subtypes of DLBCL, single-agent selinexor is demonstrating the potential to become a new oral option for this difficult-to-treat patient population who are not candidates for transplantation and whose disease is unlikely to respond to further chemotherapy or targeted agents,” Dr Maerevoet said.
Trial update
As a result of the interim data from SADAL, and in consultation with the US Food and Drug Administration (FDA), Karyopharm is amending the study protocol.
SADAL will become a single-arm study focusing solely on single-agent selinexor dosed at 60 mg twice weekly.
The study is also being amended to reduce the 14-week treatment-free period to 8 weeks in patients who achieved at least a PR on their most recent therapy. Patients who were refractory to or did not achieve at least a PR on their prior therapy will continue with the 14-week treatment-free period.
Karyopharm plans to enroll up to an additional 90 patients to the new 60 mg single-arm cohort and expects to report top-line results from the SADAL study in mid-2018.
The FDA recently lifted a partial clinical hold placed on the SADAL trial and other trials of selinexor.
The FDA had placed the hold due to a lack of information in the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.
*Data in the abstract differ from the presentation.
WASHINGTON, DC—Selinexor has demonstrated the potential to become a new oral treatment option for patients with difficult-to-treat diffuse large B-cell lymphoma (DLBCL), according to a presenter at the AACR Annual Meeting 2017.
Interim results from the phase 2b SADAL study showed that selinexor produced a 28.6% overall response rate (ORR), with an 11.1% complete response (CR) rate, in a heavily pretreated, older DLBCL population.
Responses were observed in GCB and non-GCB subtypes, and the median duration of response exceeded 7 months.
The most common adverse events (AEs) were fatigue, thrombocytopenia, nausea, anorexia, and vomiting.
Marie Maerevoet, MD, of the Institute Jules Bordet in Brussels, Belgium, presented data from the SADAL study as abstract CT132/13.*
The trial is sponsored by Karyopharm Therapeutics, the company developing selinexor.
Patients and treatment
The study enrolled 72 patients with relapsed or refractory DLBCL. At least 14 weeks had elapsed since their most recent systemic anti-DLBCL therapy.
The patients received selinexor—an oral selective inhibitor of nuclear export (SINE™) compound—at 60 mg or 100 mg twice weekly (days 1 and 3 each week) of each 28-day cycle.
60 mg arm
There were 37 patients in the 60 mg arm. Their median age was 71 (range, 38-87), and most (n=24) were male. Forty-nine percent of these patients (n=18) had GCB DLBCL.
Fourteen percent of patients had high-risk disease (according to the revised international prognostic index). Forty-three percent had high-intermediate-risk, 30% had low-intermediate-risk, and 14% had low-risk disease.
The patients had received a median of 3 prior treatment regimens (range, 2-5). Twenty-seven percent had received a prior transplant.
100 mg arm
There were 35 patients in the 100 mg arm. Their median age was 68 (range, 32-82), and most (n=23) were male. Fifty-one percent of patients (n=18) had GCB DLBCL.
Eleven percent of patients had high-risk, 40% had high-intermediate-risk, 37% had low-intermediate-risk, and 6% had low-risk disease. For 6% of patients, their risk group was unknown.
The patients had received a median of 3 prior treatment regimens (range, 2-5). Forty-six percent had received a prior transplant.
Safety
All 72 patients were evaluable for safety. The most common AEs across both dosing groups were fatigue (65%), thrombocytopenia (54%), nausea (51%), anorexia (49%), vomiting (35%), and anemia (32%).
These events were primarily grades 1 and 2 and were managed with dose modifications and/or standard supportive care.
The 60 mg dose was better tolerated than the 100 mg dose, with fewer dose interruptions and modifications required in the 60 mg arm.
Grade 3/4 AEs that were more common in the 100 mg arm than the 60 mg arm were fatigue (26% vs 11%), thrombocytopenia (46% vs 32%), and anorexia (11% vs 3%).
Efficacy
Sixty-three patients were analyzed for response. The ORR was 28.6% (18/63), with a CR rate of 11.1% (n=7) and a partial response (PR) rate of 17.5% (n=11).
The rate of stable disease (SD) was 14.3% (n=9), and the rate of progressive disease (PD) was 46% (n=29). Seven patients (11.1%) were not evaluable (NE).
The best responses as of March 1, 2017, according to subtype and selinexor dose, were as follows:
| Category | N | ORR | CR | PR | SD | PD | NE |
| 60 mg | 32 | 9 (28.1%) | 4 (12.5%) | 5 (15.6%) | 3 (9.4%) | 17 (53.1%) | 3 (9.4%) |
| 100 mg | 31 | 9 (29.0%) | 3 (9.7%) | 6 (19.4%) | 6 (19.4%) | 12 (38.7%) | 4 (12.9%) |
| GCB subtype | 32 | 8 (25.0%) | 3 (9.4%) | 5 (15.6%) | 6 (18.8%) | 13 (40.6%) | 5 (15.6%) |
| Non-GCB subtype | 31 | 10 (32.3%) | 4 (12.9%) | 6 (19.4%) | 3 (9.7%) | 16 (51.6%) | 2 (6.5%) |
The median duration of response was greater than 7 months. The median time to response was 2 months.
Among responders, the median time on treatment was 9 months, with a median follow-up of 13 months. As of the data cutoff date, 9 responders remained on treatment, including 6 patients with a CR.
The median overall survival was 8 months for all patients. As of the cutoff date, the median survival for the responders had not been reached.
“With the impressive and durable responses observed to date, including in both the GCB and non-GCB subtypes of DLBCL, single-agent selinexor is demonstrating the potential to become a new oral option for this difficult-to-treat patient population who are not candidates for transplantation and whose disease is unlikely to respond to further chemotherapy or targeted agents,” Dr Maerevoet said.
Trial update
As a result of the interim data from SADAL, and in consultation with the US Food and Drug Administration (FDA), Karyopharm is amending the study protocol.
SADAL will become a single-arm study focusing solely on single-agent selinexor dosed at 60 mg twice weekly.
The study is also being amended to reduce the 14-week treatment-free period to 8 weeks in patients who achieved at least a PR on their most recent therapy. Patients who were refractory to or did not achieve at least a PR on their prior therapy will continue with the 14-week treatment-free period.
Karyopharm plans to enroll up to an additional 90 patients to the new 60 mg single-arm cohort and expects to report top-line results from the SADAL study in mid-2018.
The FDA recently lifted a partial clinical hold placed on the SADAL trial and other trials of selinexor.
The FDA had placed the hold due to a lack of information in the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.
*Data in the abstract differ from the presentation.
Extremely short and long telomeres linked to risk of leukemia
WASHINGTON, DC—Telomere length may predict cancer risk and could be a target for future therapies, according to research presented at the AACR Annual Meeting 2017.
The study suggests that, overall, longer-than-expected telomeres are associated with an increased risk of cancer.
However, investigators also found an increased risk of certain cancers, including leukemia, among patients who had very short or very long telomeres.
“Telomeres and cancer clearly have a complex relationship,” said study investigator Jian-Min Yuan, MD, PhD, of the University of Pittsburgh Cancer Institute in Pennsylvania.
“Our hope is that by understanding this relationship, we may be able to predict which people are most likely to develop certain cancers so they can take preventive measures and perhaps be screened more often, as well as develop therapies to help our DNA keep or return its telomeres to a healthy length.”
Dr Yuan and his colleagues presented their research as abstract 2267/21.*
The team analyzed blood samples and health data on 26,540 individuals enrolled in the Singapore Chinese Health Study, which has followed the health outcomes of participants since 1993. As of the end of 2015, 4060 participants had developed cancer (77 with leukemia).
The investigators divided participants into 5 groups, based on the length of their telomeres.
The group with the longest telomeres (quartile 5) had a significantly higher risk of developing any cancer than the group with the shortest telomeres (quartile 1), after taking into account the effects of age, sex, education, body mass index, smoking habits, and alcohol consumption. The hazard ratio (HR) was 1.33 (P<0.0001).
In particular, the group with the longest telomeres had a significantly increased risk of colorectal cancer (HR=1.37, P=0.010), breast cancer (HR=1.39, P=0.007), prostate cancer (HR=1.55, P=0.011), and pancreatic cancer (HR=2.58, P=0.009).
On the other hand, the risk of liver cancer decreased as telomere length increased. The HR was 0.72 for patients in quartile 5 compared to those in quartile 1 (Plinear=0.056).
The risk of 3 cancers was greatest for both the groups with extremely short and extremely long telomeres—quartiles 1 and 5, respectively.
For leukemia, the HR was 2.15 for quartile 1 and 1.68 for quartile 5, when compared to quartile 3 (Pnon-linear=0.015).
For bladder cancer, the HRs were 1.72 and 2.17, respectively (Pnon-linear=0.01). And for stomach cancer, the HRs were 1.63 and 1.55, respectively (Pnon-linear=0.020).
“We had the idea for this study more than 7 years ago, but it took the laboratory 3 months to finish quantifying telomere length for just 100 samples, which was not enough to draw any meaningful conclusions,” Dr Yuan said.
“Not even a decade later, we’ve been able to run nearly 30,000 samples in a year and draw these really robust insights, showing how far technology has come. Even more complicated will be linking telomere length to genome-wide analyses, which is on the horizon. We’re on the cusp of gaining a truly remarkable understanding of the complicated biological phenomena that lead to cancer.”
*The presentation differed from the abstract.
WASHINGTON, DC—Telomere length may predict cancer risk and could be a target for future therapies, according to research presented at the AACR Annual Meeting 2017.
The study suggests that, overall, longer-than-expected telomeres are associated with an increased risk of cancer.
However, investigators also found an increased risk of certain cancers, including leukemia, among patients who had very short or very long telomeres.
“Telomeres and cancer clearly have a complex relationship,” said study investigator Jian-Min Yuan, MD, PhD, of the University of Pittsburgh Cancer Institute in Pennsylvania.
“Our hope is that by understanding this relationship, we may be able to predict which people are most likely to develop certain cancers so they can take preventive measures and perhaps be screened more often, as well as develop therapies to help our DNA keep or return its telomeres to a healthy length.”
Dr Yuan and his colleagues presented their research as abstract 2267/21.*
The team analyzed blood samples and health data on 26,540 individuals enrolled in the Singapore Chinese Health Study, which has followed the health outcomes of participants since 1993. As of the end of 2015, 4060 participants had developed cancer (77 with leukemia).
The investigators divided participants into 5 groups, based on the length of their telomeres.
The group with the longest telomeres (quartile 5) had a significantly higher risk of developing any cancer than the group with the shortest telomeres (quartile 1), after taking into account the effects of age, sex, education, body mass index, smoking habits, and alcohol consumption. The hazard ratio (HR) was 1.33 (P<0.0001).
In particular, the group with the longest telomeres had a significantly increased risk of colorectal cancer (HR=1.37, P=0.010), breast cancer (HR=1.39, P=0.007), prostate cancer (HR=1.55, P=0.011), and pancreatic cancer (HR=2.58, P=0.009).
On the other hand, the risk of liver cancer decreased as telomere length increased. The HR was 0.72 for patients in quartile 5 compared to those in quartile 1 (Plinear=0.056).
The risk of 3 cancers was greatest for both the groups with extremely short and extremely long telomeres—quartiles 1 and 5, respectively.
For leukemia, the HR was 2.15 for quartile 1 and 1.68 for quartile 5, when compared to quartile 3 (Pnon-linear=0.015).
For bladder cancer, the HRs were 1.72 and 2.17, respectively (Pnon-linear=0.01). And for stomach cancer, the HRs were 1.63 and 1.55, respectively (Pnon-linear=0.020).
“We had the idea for this study more than 7 years ago, but it took the laboratory 3 months to finish quantifying telomere length for just 100 samples, which was not enough to draw any meaningful conclusions,” Dr Yuan said.
“Not even a decade later, we’ve been able to run nearly 30,000 samples in a year and draw these really robust insights, showing how far technology has come. Even more complicated will be linking telomere length to genome-wide analyses, which is on the horizon. We’re on the cusp of gaining a truly remarkable understanding of the complicated biological phenomena that lead to cancer.”
*The presentation differed from the abstract.
WASHINGTON, DC—Telomere length may predict cancer risk and could be a target for future therapies, according to research presented at the AACR Annual Meeting 2017.
The study suggests that, overall, longer-than-expected telomeres are associated with an increased risk of cancer.
However, investigators also found an increased risk of certain cancers, including leukemia, among patients who had very short or very long telomeres.
“Telomeres and cancer clearly have a complex relationship,” said study investigator Jian-Min Yuan, MD, PhD, of the University of Pittsburgh Cancer Institute in Pennsylvania.
“Our hope is that by understanding this relationship, we may be able to predict which people are most likely to develop certain cancers so they can take preventive measures and perhaps be screened more often, as well as develop therapies to help our DNA keep or return its telomeres to a healthy length.”
Dr Yuan and his colleagues presented their research as abstract 2267/21.*
The team analyzed blood samples and health data on 26,540 individuals enrolled in the Singapore Chinese Health Study, which has followed the health outcomes of participants since 1993. As of the end of 2015, 4060 participants had developed cancer (77 with leukemia).
The investigators divided participants into 5 groups, based on the length of their telomeres.
The group with the longest telomeres (quartile 5) had a significantly higher risk of developing any cancer than the group with the shortest telomeres (quartile 1), after taking into account the effects of age, sex, education, body mass index, smoking habits, and alcohol consumption. The hazard ratio (HR) was 1.33 (P<0.0001).
In particular, the group with the longest telomeres had a significantly increased risk of colorectal cancer (HR=1.37, P=0.010), breast cancer (HR=1.39, P=0.007), prostate cancer (HR=1.55, P=0.011), and pancreatic cancer (HR=2.58, P=0.009).
On the other hand, the risk of liver cancer decreased as telomere length increased. The HR was 0.72 for patients in quartile 5 compared to those in quartile 1 (Plinear=0.056).
The risk of 3 cancers was greatest for both the groups with extremely short and extremely long telomeres—quartiles 1 and 5, respectively.
For leukemia, the HR was 2.15 for quartile 1 and 1.68 for quartile 5, when compared to quartile 3 (Pnon-linear=0.015).
For bladder cancer, the HRs were 1.72 and 2.17, respectively (Pnon-linear=0.01). And for stomach cancer, the HRs were 1.63 and 1.55, respectively (Pnon-linear=0.020).
“We had the idea for this study more than 7 years ago, but it took the laboratory 3 months to finish quantifying telomere length for just 100 samples, which was not enough to draw any meaningful conclusions,” Dr Yuan said.
“Not even a decade later, we’ve been able to run nearly 30,000 samples in a year and draw these really robust insights, showing how far technology has come. Even more complicated will be linking telomere length to genome-wide analyses, which is on the horizon. We’re on the cusp of gaining a truly remarkable understanding of the complicated biological phenomena that lead to cancer.”
*The presentation differed from the abstract.