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Group develops MM-specific CAR T-cell therapy
Researchers say they have identified a multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) T-cell therapy.
The team unearthed an MM-specific monoclonal antibody (mAb) and designed a CAR that incorporates a fragment derived from that mAb.
The resulting CAR T-cell therapy exhibited anti-MM activity in vitro and in vivo but did not have a negative effect on normal hematopoietic cells.
The researchers described this work in Nature Medicine.
The team believed that new antigen epitopes could be discovered by thoroughly searching for cancer-specific mAbs and characterizing the antigens they recognize.
“We applied this strategy to identify novel therapeutic targets for multiple myeloma . . . ,” explained study author Naoki Hosen, MD, PhD, of Osaka University in Osaka, Japan.
The researchers screened more than 10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb that recognizes a subset of integrin β7 molecules.
The team found that MMG49 reacted to MM cells—but not to normal hematopoietic cells—in MM patient samples.
This prompted the researchers to design a CAR that incorporates a fragment derived from MMG49.
When tested in vitro, MMG49 CAR T cells exhibited cytotoxic activity against cell lines expressing the MMG49 epitope and primary MM cell from patients’ bone marrow. However, MMG49 CAR T cells did not have cytotoxic effects on MMG49-negative cells or normal hematopoietic cells.
The researchers said MM cells were completely eradicated by MMG49 CAR T cells. But the therapy did not kill T cells, even when integrin β7 was activated by MAdCAM-1 and CXCL12.
In mouse models of MM, MMG49 CAR T cells significantly prolonged survival when compared to a CD19 CAR T-cell therapy. MMG49 CAR T cells eradicated MM cells and significantly decreased tumor burden in some mice, but some mice relapsed.
MMG49 CAR T cells did not affect normal hematopoietic cells in the mice, and the researchers said there were no unexpected side effects with the treatment.
“Our results also demonstrate that the active conformer of integrin β7 can serve as an immunotherapeutic target against MM, even though the expression of the protein itself is not specific to MM,” said study author Yukiko Matsunaga, PhD, of Princess Margaret Cancer Centre, University Health Network, in Toronto, Canada.
“Therefore, it’s highly plausible that there are other cancer immunotherapeutic targets that have yet to be identified in many cell-surface proteins that undergo conformational changes, even if the expression of the proteins themselves is not cancer-specific.” 
Researchers say they have identified a multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) T-cell therapy.
The team unearthed an MM-specific monoclonal antibody (mAb) and designed a CAR that incorporates a fragment derived from that mAb.
The resulting CAR T-cell therapy exhibited anti-MM activity in vitro and in vivo but did not have a negative effect on normal hematopoietic cells.
The researchers described this work in Nature Medicine.
The team believed that new antigen epitopes could be discovered by thoroughly searching for cancer-specific mAbs and characterizing the antigens they recognize.
“We applied this strategy to identify novel therapeutic targets for multiple myeloma . . . ,” explained study author Naoki Hosen, MD, PhD, of Osaka University in Osaka, Japan.
The researchers screened more than 10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb that recognizes a subset of integrin β7 molecules.
The team found that MMG49 reacted to MM cells—but not to normal hematopoietic cells—in MM patient samples.
This prompted the researchers to design a CAR that incorporates a fragment derived from MMG49.
When tested in vitro, MMG49 CAR T cells exhibited cytotoxic activity against cell lines expressing the MMG49 epitope and primary MM cell from patients’ bone marrow. However, MMG49 CAR T cells did not have cytotoxic effects on MMG49-negative cells or normal hematopoietic cells.
The researchers said MM cells were completely eradicated by MMG49 CAR T cells. But the therapy did not kill T cells, even when integrin β7 was activated by MAdCAM-1 and CXCL12.
In mouse models of MM, MMG49 CAR T cells significantly prolonged survival when compared to a CD19 CAR T-cell therapy. MMG49 CAR T cells eradicated MM cells and significantly decreased tumor burden in some mice, but some mice relapsed.
MMG49 CAR T cells did not affect normal hematopoietic cells in the mice, and the researchers said there were no unexpected side effects with the treatment.
“Our results also demonstrate that the active conformer of integrin β7 can serve as an immunotherapeutic target against MM, even though the expression of the protein itself is not specific to MM,” said study author Yukiko Matsunaga, PhD, of Princess Margaret Cancer Centre, University Health Network, in Toronto, Canada.
“Therefore, it’s highly plausible that there are other cancer immunotherapeutic targets that have yet to be identified in many cell-surface proteins that undergo conformational changes, even if the expression of the proteins themselves is not cancer-specific.”
Researchers say they have identified a multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) T-cell therapy.
The team unearthed an MM-specific monoclonal antibody (mAb) and designed a CAR that incorporates a fragment derived from that mAb.
The resulting CAR T-cell therapy exhibited anti-MM activity in vitro and in vivo but did not have a negative effect on normal hematopoietic cells.
The researchers described this work in Nature Medicine.
The team believed that new antigen epitopes could be discovered by thoroughly searching for cancer-specific mAbs and characterizing the antigens they recognize.
“We applied this strategy to identify novel therapeutic targets for multiple myeloma . . . ,” explained study author Naoki Hosen, MD, PhD, of Osaka University in Osaka, Japan.
The researchers screened more than 10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb that recognizes a subset of integrin β7 molecules.
The team found that MMG49 reacted to MM cells—but not to normal hematopoietic cells—in MM patient samples.
This prompted the researchers to design a CAR that incorporates a fragment derived from MMG49.
When tested in vitro, MMG49 CAR T cells exhibited cytotoxic activity against cell lines expressing the MMG49 epitope and primary MM cell from patients’ bone marrow. However, MMG49 CAR T cells did not have cytotoxic effects on MMG49-negative cells or normal hematopoietic cells.
The researchers said MM cells were completely eradicated by MMG49 CAR T cells. But the therapy did not kill T cells, even when integrin β7 was activated by MAdCAM-1 and CXCL12.
In mouse models of MM, MMG49 CAR T cells significantly prolonged survival when compared to a CD19 CAR T-cell therapy. MMG49 CAR T cells eradicated MM cells and significantly decreased tumor burden in some mice, but some mice relapsed.
MMG49 CAR T cells did not affect normal hematopoietic cells in the mice, and the researchers said there were no unexpected side effects with the treatment.
“Our results also demonstrate that the active conformer of integrin β7 can serve as an immunotherapeutic target against MM, even though the expression of the protein itself is not specific to MM,” said study author Yukiko Matsunaga, PhD, of Princess Margaret Cancer Centre, University Health Network, in Toronto, Canada.
“Therefore, it’s highly plausible that there are other cancer immunotherapeutic targets that have yet to be identified in many cell-surface proteins that undergo conformational changes, even if the expression of the proteins themselves is not cancer-specific.”
Mogamulizumab BLA receives priority review
The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for mogamulizumab.
Mogamulizumab is a humanized monoclonal antibody directed against CCR4 that is being developed by Kyowa Hakko Kirin Co., Ltd.
The company is seeking FDA approval for mogamulizumab as a treatment for patients with cutaneous T-cell lymphoma (CTCL) who have received at least 1 prior systemic therapy.
The FDA expects to make a decision on the BLA by June 4, 2018.
The FDA’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The BLA for mogamulizumab is supported by data from the MAVORIC study, the largest global randomized clinical trial of systemic therapy in CTCL.
MAVORIC is a phase 3 trial in which researchers evaluated mogamulizumab and an active comparator in 372 patients with CTCL who had failed at least 1 prior systemic treatment. The study was conducted in the US, Europe, Japan, and Australia.
Results from this trial are scheduled to be presented at the 2017 ASH Annual Meeting (abstract 817).
The FDA previously granted mogamulizumab breakthrough therapy designation as a treatment for CTCL patients who have received at least 1 prior systemic therapy.
Breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions. The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for mogamulizumab.
Mogamulizumab is a humanized monoclonal antibody directed against CCR4 that is being developed by Kyowa Hakko Kirin Co., Ltd.
The company is seeking FDA approval for mogamulizumab as a treatment for patients with cutaneous T-cell lymphoma (CTCL) who have received at least 1 prior systemic therapy.
The FDA expects to make a decision on the BLA by June 4, 2018.
The FDA’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The BLA for mogamulizumab is supported by data from the MAVORIC study, the largest global randomized clinical trial of systemic therapy in CTCL.
MAVORIC is a phase 3 trial in which researchers evaluated mogamulizumab and an active comparator in 372 patients with CTCL who had failed at least 1 prior systemic treatment. The study was conducted in the US, Europe, Japan, and Australia.
Results from this trial are scheduled to be presented at the 2017 ASH Annual Meeting (abstract 817).
The FDA previously granted mogamulizumab breakthrough therapy designation as a treatment for CTCL patients who have received at least 1 prior systemic therapy.
Breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions. The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for mogamulizumab.
Mogamulizumab is a humanized monoclonal antibody directed against CCR4 that is being developed by Kyowa Hakko Kirin Co., Ltd.
The company is seeking FDA approval for mogamulizumab as a treatment for patients with cutaneous T-cell lymphoma (CTCL) who have received at least 1 prior systemic therapy.
The FDA expects to make a decision on the BLA by June 4, 2018.
The FDA’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The BLA for mogamulizumab is supported by data from the MAVORIC study, the largest global randomized clinical trial of systemic therapy in CTCL.
MAVORIC is a phase 3 trial in which researchers evaluated mogamulizumab and an active comparator in 372 patients with CTCL who had failed at least 1 prior systemic treatment. The study was conducted in the US, Europe, Japan, and Australia.
Results from this trial are scheduled to be presented at the 2017 ASH Annual Meeting (abstract 817).
The FDA previously granted mogamulizumab breakthrough therapy designation as a treatment for CTCL patients who have received at least 1 prior systemic therapy.
Breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions. The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
FDA grants priority review to NDA for avatrombopag
The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for avatrombopag.
Avatrombopag is a second-generation thrombopoietin receptor agonist that is intended to address the limitations of existing treatments for thrombocytopenia.
With this NDA, Dova Pharmaceuticals, Inc., is seeking approval of avatrombopag for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure.
The FDA expects to make a decision on the NDA by May 21, 2018.
The FDA’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
Phase 3 trials
The NDA submission for avatrombopag is supported by 2 identically designed phase 3 trials, ADAPT 1 and ADAPT 2. Results from these trials were presented at the 2017 American Association for the Study of Liver Disease (AASLD) Meeting last month (abstract 217).
The studies randomized 435 patients with thrombocytopenia and chronic liver disease who were scheduled to undergo a procedure.
Patients with low baseline platelet counts (<40x 109/L) were randomized to receive 60 mg of avatrombopag or placebo daily for 5 days.
Patients with higher baseline platelet counts (40 to <50 x 109/L) were randomized to receive 40 mg of avatrombopag or placebo daily for 5 days.
Patients underwent their procedures 5 to 8 days after their last dose of avatrombopag.
In ADAPT-1, 85 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 78 controls completed the study.
In ADAPT-2, 68 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 68 controls completed the study.
Efficacy
The primary efficacy endpoint of these trials was the proportion of patients who did not require any bleeding rescue up to 7 days post-procedure. Bleeding rescue included platelet transfusion, fresh frozen plasma, cryoprecipitate, vitamin K (phytonadione), desmopressin, recombinant activated factor VII, aminocaproicacid, tranexamic acid, whole blood transfusion, packed red cell transfusion, surgical intervention, or interventional radiology.
In ADAPT-1, the primary endpoint was achieved by 66% of patients who received avatrombopag at 60 mg and 23% of those who received placebo in the low-platelet-count cohort (P<0.0001). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 38% of controls in the higher-platelet-count cohort (P<0.0001).
In ADAPT-2, the primary endpoint was achieved by 69% of patients who received avatrombopag at 60 mg and 35% of those who received placebo in the low-platelet-count cohort (P<0.0006). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 33% of controls in the higher- platelet-count cohort (P<0.0001).
A secondary efficacy endpoint was the proportion of patients achieving the target platelet count (≥50 x 109/L).
In ADAPT-1, this endpoint was met by 69% of patients who received avatrombopag at 60 mg and 4% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 88% of patients who received avatrombopag at 40 mg and 21% of controls in the higher-platelet-count cohort (P<0.0001)
In ADAPT-2, this endpoint was met by 67% of patients who received avatrombopag at 60 mg and 7% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 93% of patients who received avatrombopag at 40 mg and 39% of controls in the higher-platelet-count cohort (P<0.0001).
Safety
The researchers pooled safety data from the 2 trials.
Treatment-emergent adverse events (AEs) occurred in 58.2% of controls and 56% of avatrombopag-treated patients in the low-platelet-count cohort (60 mg). Treatment-emergent AEs also occurred in 50.8% of controls and 51.3% of avatrombopag-treated patients in the higher-platelet-count cohort (40 mg).
The most frequently reported treatment-emergent AEs were pyrexia, abdominal pain, nausea, headache, diarrhea, and fatigue.
One patient experienced partial portal vein thrombosis that was considered non-serious and potentially related to avatrombopag.
Treatment-related AEs occurred in 17.6% of controls and 11.3% of avatrombopag-treated patients in the low-platelet-count cohort. Treatment-related AEs also occurred in 6.2% of controls and 7% of avatrombopag-treated patients in the higher-platelet-count cohort.
Serious AEs occurred in 13.2%, 6.9%, 3.1%, and 7.8%, respectively.
There were 3 deaths—2 in the 40 mg avatrombopag arm in ADAPT-1 and 1 in the control group in ADAPT-2. None of the deaths was considered treatment-related.
Future directions
Dova Pharmaceuticals, Inc., is planning to explore the potential use of avatrombopag in a broader population of patients with thrombocytopenia. This includes patients undergoing surgical procedures associated with a high risk of bleeding and patients who develop thrombocytopenia after receiving chemotherapy.
In addition, the company is exploring a potential regulatory approval pathway for avatrombopag for the treatment of adults with chronic immune thrombocytopenic purpura based on results from a completed phase 3 trial in this patient population.
The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for avatrombopag.
Avatrombopag is a second-generation thrombopoietin receptor agonist that is intended to address the limitations of existing treatments for thrombocytopenia.
With this NDA, Dova Pharmaceuticals, Inc., is seeking approval of avatrombopag for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure.
The FDA expects to make a decision on the NDA by May 21, 2018.
The FDA’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
Phase 3 trials
The NDA submission for avatrombopag is supported by 2 identically designed phase 3 trials, ADAPT 1 and ADAPT 2. Results from these trials were presented at the 2017 American Association for the Study of Liver Disease (AASLD) Meeting last month (abstract 217).
The studies randomized 435 patients with thrombocytopenia and chronic liver disease who were scheduled to undergo a procedure.
Patients with low baseline platelet counts (<40x 109/L) were randomized to receive 60 mg of avatrombopag or placebo daily for 5 days.
Patients with higher baseline platelet counts (40 to <50 x 109/L) were randomized to receive 40 mg of avatrombopag or placebo daily for 5 days.
Patients underwent their procedures 5 to 8 days after their last dose of avatrombopag.
In ADAPT-1, 85 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 78 controls completed the study.
In ADAPT-2, 68 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 68 controls completed the study.
Efficacy
The primary efficacy endpoint of these trials was the proportion of patients who did not require any bleeding rescue up to 7 days post-procedure. Bleeding rescue included platelet transfusion, fresh frozen plasma, cryoprecipitate, vitamin K (phytonadione), desmopressin, recombinant activated factor VII, aminocaproicacid, tranexamic acid, whole blood transfusion, packed red cell transfusion, surgical intervention, or interventional radiology.
In ADAPT-1, the primary endpoint was achieved by 66% of patients who received avatrombopag at 60 mg and 23% of those who received placebo in the low-platelet-count cohort (P<0.0001). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 38% of controls in the higher-platelet-count cohort (P<0.0001).
In ADAPT-2, the primary endpoint was achieved by 69% of patients who received avatrombopag at 60 mg and 35% of those who received placebo in the low-platelet-count cohort (P<0.0006). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 33% of controls in the higher- platelet-count cohort (P<0.0001).
A secondary efficacy endpoint was the proportion of patients achieving the target platelet count (≥50 x 109/L).
In ADAPT-1, this endpoint was met by 69% of patients who received avatrombopag at 60 mg and 4% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 88% of patients who received avatrombopag at 40 mg and 21% of controls in the higher-platelet-count cohort (P<0.0001)
In ADAPT-2, this endpoint was met by 67% of patients who received avatrombopag at 60 mg and 7% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 93% of patients who received avatrombopag at 40 mg and 39% of controls in the higher-platelet-count cohort (P<0.0001).
Safety
The researchers pooled safety data from the 2 trials.
Treatment-emergent adverse events (AEs) occurred in 58.2% of controls and 56% of avatrombopag-treated patients in the low-platelet-count cohort (60 mg). Treatment-emergent AEs also occurred in 50.8% of controls and 51.3% of avatrombopag-treated patients in the higher-platelet-count cohort (40 mg).
The most frequently reported treatment-emergent AEs were pyrexia, abdominal pain, nausea, headache, diarrhea, and fatigue.
One patient experienced partial portal vein thrombosis that was considered non-serious and potentially related to avatrombopag.
Treatment-related AEs occurred in 17.6% of controls and 11.3% of avatrombopag-treated patients in the low-platelet-count cohort. Treatment-related AEs also occurred in 6.2% of controls and 7% of avatrombopag-treated patients in the higher-platelet-count cohort.
Serious AEs occurred in 13.2%, 6.9%, 3.1%, and 7.8%, respectively.
There were 3 deaths—2 in the 40 mg avatrombopag arm in ADAPT-1 and 1 in the control group in ADAPT-2. None of the deaths was considered treatment-related.
Future directions
Dova Pharmaceuticals, Inc., is planning to explore the potential use of avatrombopag in a broader population of patients with thrombocytopenia. This includes patients undergoing surgical procedures associated with a high risk of bleeding and patients who develop thrombocytopenia after receiving chemotherapy.
In addition, the company is exploring a potential regulatory approval pathway for avatrombopag for the treatment of adults with chronic immune thrombocytopenic purpura based on results from a completed phase 3 trial in this patient population.
The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for avatrombopag.
Avatrombopag is a second-generation thrombopoietin receptor agonist that is intended to address the limitations of existing treatments for thrombocytopenia.
With this NDA, Dova Pharmaceuticals, Inc., is seeking approval of avatrombopag for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure.
The FDA expects to make a decision on the NDA by May 21, 2018.
The FDA’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
Phase 3 trials
The NDA submission for avatrombopag is supported by 2 identically designed phase 3 trials, ADAPT 1 and ADAPT 2. Results from these trials were presented at the 2017 American Association for the Study of Liver Disease (AASLD) Meeting last month (abstract 217).
The studies randomized 435 patients with thrombocytopenia and chronic liver disease who were scheduled to undergo a procedure.
Patients with low baseline platelet counts (<40x 109/L) were randomized to receive 60 mg of avatrombopag or placebo daily for 5 days.
Patients with higher baseline platelet counts (40 to <50 x 109/L) were randomized to receive 40 mg of avatrombopag or placebo daily for 5 days.
Patients underwent their procedures 5 to 8 days after their last dose of avatrombopag.
In ADAPT-1, 85 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 78 controls completed the study.
In ADAPT-2, 68 patients completed treatment with avatrombopag at 60 mg, 55 completed treatment with avatrombopag at 40 mg, and 68 controls completed the study.
Efficacy
The primary efficacy endpoint of these trials was the proportion of patients who did not require any bleeding rescue up to 7 days post-procedure. Bleeding rescue included platelet transfusion, fresh frozen plasma, cryoprecipitate, vitamin K (phytonadione), desmopressin, recombinant activated factor VII, aminocaproicacid, tranexamic acid, whole blood transfusion, packed red cell transfusion, surgical intervention, or interventional radiology.
In ADAPT-1, the primary endpoint was achieved by 66% of patients who received avatrombopag at 60 mg and 23% of those who received placebo in the low-platelet-count cohort (P<0.0001). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 38% of controls in the higher-platelet-count cohort (P<0.0001).
In ADAPT-2, the primary endpoint was achieved by 69% of patients who received avatrombopag at 60 mg and 35% of those who received placebo in the low-platelet-count cohort (P<0.0006). The endpoint was also achieved by 88% of patients who received avatrombopag at 40 mg and 33% of controls in the higher- platelet-count cohort (P<0.0001).
A secondary efficacy endpoint was the proportion of patients achieving the target platelet count (≥50 x 109/L).
In ADAPT-1, this endpoint was met by 69% of patients who received avatrombopag at 60 mg and 4% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 88% of patients who received avatrombopag at 40 mg and 21% of controls in the higher-platelet-count cohort (P<0.0001)
In ADAPT-2, this endpoint was met by 67% of patients who received avatrombopag at 60 mg and 7% of controls in the low-platelet-count cohort (P<0.0001). It was also met by 93% of patients who received avatrombopag at 40 mg and 39% of controls in the higher-platelet-count cohort (P<0.0001).
Safety
The researchers pooled safety data from the 2 trials.
Treatment-emergent adverse events (AEs) occurred in 58.2% of controls and 56% of avatrombopag-treated patients in the low-platelet-count cohort (60 mg). Treatment-emergent AEs also occurred in 50.8% of controls and 51.3% of avatrombopag-treated patients in the higher-platelet-count cohort (40 mg).
The most frequently reported treatment-emergent AEs were pyrexia, abdominal pain, nausea, headache, diarrhea, and fatigue.
One patient experienced partial portal vein thrombosis that was considered non-serious and potentially related to avatrombopag.
Treatment-related AEs occurred in 17.6% of controls and 11.3% of avatrombopag-treated patients in the low-platelet-count cohort. Treatment-related AEs also occurred in 6.2% of controls and 7% of avatrombopag-treated patients in the higher-platelet-count cohort.
Serious AEs occurred in 13.2%, 6.9%, 3.1%, and 7.8%, respectively.
There were 3 deaths—2 in the 40 mg avatrombopag arm in ADAPT-1 and 1 in the control group in ADAPT-2. None of the deaths was considered treatment-related.
Future directions
Dova Pharmaceuticals, Inc., is planning to explore the potential use of avatrombopag in a broader population of patients with thrombocytopenia. This includes patients undergoing surgical procedures associated with a high risk of bleeding and patients who develop thrombocytopenia after receiving chemotherapy.
In addition, the company is exploring a potential regulatory approval pathway for avatrombopag for the treatment of adults with chronic immune thrombocytopenic purpura based on results from a completed phase 3 trial in this patient population.
Study reveals predictor of early mortality in AML
New research has shown an increased risk of early death in patients with acute myeloid leukemia (AML) who have high levels of indoleamine 2,3 dioxygenase-1 (IDO-1), an enzyme known to suppress the immune system.
Researchers quantified IDO-1 expression in diagnostic samples from patients with AML and discovered that high levels of IDO-1 were significantly associated with induction failure and poor overall survival (OS).
Ravindra Kolhe, MD, PhD, of the Medical College of Georgia at Augusta University, and his colleagues recounted these findings in Scientific Reports.
The researchers reviewed data from 40 AML patients. They had a median age at diagnosis of 60 (range, 27–89), 60% were female, and 55% were self-reported as Caucasian.
Most patients (72.5%) received standard anthracycline and cytarabine as induction, 10% received hypomethylating agents, and 17.5% were untreated or had unknown treatment status.
Fifteen percent of patients underwent allogeneic hematopoietic stem cell transplant (allo-HSCT) at the time of first complete remission.
Half of all patients achieved remission, and half of those patients (n=10, 25%) had a subsequent relapse. The median OS was 283 days (range, 32–1941). Twenty percent of patients (n=8) were still alive at the time of data analysis.
IDO-1 analysis
“We wanted to look at what makes this leukemia so aggressive that initial induction chemotherapy is not working,” Dr Kolhe said. “Early relapse tends to predict early mortality in these patients, and one of the things we looked at was IDO.”
The researchers extracted IDO-1 mRNA from diagnostic bone marrow samples from 29 of the patients but assessed IDO-1 protein expression in all 40 patients via immunohistochemistry.
The team quantified IDO-1 expression using a “composite IDO-1 score.” They used a cut-off point of 0.45 and divided patients’ samples into 2 groups: high (≥0.45) and low (<0.45) IDO-1 score.
The researchers compared IDO-1 results across 4 survival groups, which included patients surviving:
- Less than 6 months
- More than 6 months to 1 year
- More than 1 year to less than 5 years
- Beyond 5 years.
The team found a direct correlation between poor OS and higher composite IDO-1 score (P=0.0005).
“The patients who died at 6 months had a high expression of IDO, while the blasts produced relatively little IDO in the patients who lived 5 years or more,” Dr Kolhe said.
Independent predictor
The researchers conducted a univariate analysis and identified several factors that were significantly associated with poor OS, including:
- Higher IDO-1 mRNA (P=0.005)
- Higher composite IDO-1 score (P<0.0001)
- Higher age (P=0.0018)
- Male gender (P=0.019)
- High-risk cytogenetics (P=0.002)
- Not undergoing allo-HSCT (P=0.0005).
In a multivariate analysis including the above variables, the researchers found that a higher composite IDO-1 score (P=0.007) and not undergoing allo-HSCT (P=0.007) were significantly associated with poor OS.
The team also found that patients who failed induction had a higher composite IDO-1 score (P=0.01).
“Most of the time, we don’t know why patients are not responding to chemotherapy,” Dr Kolhe noted. “But when the researchers adjusted for other risk factors for AML, like increased age and severe anemia, IDO levels were a standout. Right now, we know it’s high in patients who die at 6 months, and we show that it’s an independent indicator if you adjust for other known variables.”
Dr Kolhe said these results suggest IDO-1 expression should be measured when the diagnostic bone marrow biopsy is performed. This may help identify AML patients who could benefit from receiving an IDO inhibitor along with standard therapy.
Researchers are currently conducting a phase 1/2 trial of the IDO inhibitor indoximod in combination with idarubicin and cytarabine in patients with newly diagnosed AML (NCT02835729).
New research has shown an increased risk of early death in patients with acute myeloid leukemia (AML) who have high levels of indoleamine 2,3 dioxygenase-1 (IDO-1), an enzyme known to suppress the immune system.
Researchers quantified IDO-1 expression in diagnostic samples from patients with AML and discovered that high levels of IDO-1 were significantly associated with induction failure and poor overall survival (OS).
Ravindra Kolhe, MD, PhD, of the Medical College of Georgia at Augusta University, and his colleagues recounted these findings in Scientific Reports.
The researchers reviewed data from 40 AML patients. They had a median age at diagnosis of 60 (range, 27–89), 60% were female, and 55% were self-reported as Caucasian.
Most patients (72.5%) received standard anthracycline and cytarabine as induction, 10% received hypomethylating agents, and 17.5% were untreated or had unknown treatment status.
Fifteen percent of patients underwent allogeneic hematopoietic stem cell transplant (allo-HSCT) at the time of first complete remission.
Half of all patients achieved remission, and half of those patients (n=10, 25%) had a subsequent relapse. The median OS was 283 days (range, 32–1941). Twenty percent of patients (n=8) were still alive at the time of data analysis.
IDO-1 analysis
“We wanted to look at what makes this leukemia so aggressive that initial induction chemotherapy is not working,” Dr Kolhe said. “Early relapse tends to predict early mortality in these patients, and one of the things we looked at was IDO.”
The researchers extracted IDO-1 mRNA from diagnostic bone marrow samples from 29 of the patients but assessed IDO-1 protein expression in all 40 patients via immunohistochemistry.
The team quantified IDO-1 expression using a “composite IDO-1 score.” They used a cut-off point of 0.45 and divided patients’ samples into 2 groups: high (≥0.45) and low (<0.45) IDO-1 score.
The researchers compared IDO-1 results across 4 survival groups, which included patients surviving:
- Less than 6 months
- More than 6 months to 1 year
- More than 1 year to less than 5 years
- Beyond 5 years.
The team found a direct correlation between poor OS and higher composite IDO-1 score (P=0.0005).
“The patients who died at 6 months had a high expression of IDO, while the blasts produced relatively little IDO in the patients who lived 5 years or more,” Dr Kolhe said.
Independent predictor
The researchers conducted a univariate analysis and identified several factors that were significantly associated with poor OS, including:
- Higher IDO-1 mRNA (P=0.005)
- Higher composite IDO-1 score (P<0.0001)
- Higher age (P=0.0018)
- Male gender (P=0.019)
- High-risk cytogenetics (P=0.002)
- Not undergoing allo-HSCT (P=0.0005).
In a multivariate analysis including the above variables, the researchers found that a higher composite IDO-1 score (P=0.007) and not undergoing allo-HSCT (P=0.007) were significantly associated with poor OS.
The team also found that patients who failed induction had a higher composite IDO-1 score (P=0.01).
“Most of the time, we don’t know why patients are not responding to chemotherapy,” Dr Kolhe noted. “But when the researchers adjusted for other risk factors for AML, like increased age and severe anemia, IDO levels were a standout. Right now, we know it’s high in patients who die at 6 months, and we show that it’s an independent indicator if you adjust for other known variables.”
Dr Kolhe said these results suggest IDO-1 expression should be measured when the diagnostic bone marrow biopsy is performed. This may help identify AML patients who could benefit from receiving an IDO inhibitor along with standard therapy.
Researchers are currently conducting a phase 1/2 trial of the IDO inhibitor indoximod in combination with idarubicin and cytarabine in patients with newly diagnosed AML (NCT02835729).
New research has shown an increased risk of early death in patients with acute myeloid leukemia (AML) who have high levels of indoleamine 2,3 dioxygenase-1 (IDO-1), an enzyme known to suppress the immune system.
Researchers quantified IDO-1 expression in diagnostic samples from patients with AML and discovered that high levels of IDO-1 were significantly associated with induction failure and poor overall survival (OS).
Ravindra Kolhe, MD, PhD, of the Medical College of Georgia at Augusta University, and his colleagues recounted these findings in Scientific Reports.
The researchers reviewed data from 40 AML patients. They had a median age at diagnosis of 60 (range, 27–89), 60% were female, and 55% were self-reported as Caucasian.
Most patients (72.5%) received standard anthracycline and cytarabine as induction, 10% received hypomethylating agents, and 17.5% were untreated or had unknown treatment status.
Fifteen percent of patients underwent allogeneic hematopoietic stem cell transplant (allo-HSCT) at the time of first complete remission.
Half of all patients achieved remission, and half of those patients (n=10, 25%) had a subsequent relapse. The median OS was 283 days (range, 32–1941). Twenty percent of patients (n=8) were still alive at the time of data analysis.
IDO-1 analysis
“We wanted to look at what makes this leukemia so aggressive that initial induction chemotherapy is not working,” Dr Kolhe said. “Early relapse tends to predict early mortality in these patients, and one of the things we looked at was IDO.”
The researchers extracted IDO-1 mRNA from diagnostic bone marrow samples from 29 of the patients but assessed IDO-1 protein expression in all 40 patients via immunohistochemistry.
The team quantified IDO-1 expression using a “composite IDO-1 score.” They used a cut-off point of 0.45 and divided patients’ samples into 2 groups: high (≥0.45) and low (<0.45) IDO-1 score.
The researchers compared IDO-1 results across 4 survival groups, which included patients surviving:
- Less than 6 months
- More than 6 months to 1 year
- More than 1 year to less than 5 years
- Beyond 5 years.
The team found a direct correlation between poor OS and higher composite IDO-1 score (P=0.0005).
“The patients who died at 6 months had a high expression of IDO, while the blasts produced relatively little IDO in the patients who lived 5 years or more,” Dr Kolhe said.
Independent predictor
The researchers conducted a univariate analysis and identified several factors that were significantly associated with poor OS, including:
- Higher IDO-1 mRNA (P=0.005)
- Higher composite IDO-1 score (P<0.0001)
- Higher age (P=0.0018)
- Male gender (P=0.019)
- High-risk cytogenetics (P=0.002)
- Not undergoing allo-HSCT (P=0.0005).
In a multivariate analysis including the above variables, the researchers found that a higher composite IDO-1 score (P=0.007) and not undergoing allo-HSCT (P=0.007) were significantly associated with poor OS.
The team also found that patients who failed induction had a higher composite IDO-1 score (P=0.01).
“Most of the time, we don’t know why patients are not responding to chemotherapy,” Dr Kolhe noted. “But when the researchers adjusted for other risk factors for AML, like increased age and severe anemia, IDO levels were a standout. Right now, we know it’s high in patients who die at 6 months, and we show that it’s an independent indicator if you adjust for other known variables.”
Dr Kolhe said these results suggest IDO-1 expression should be measured when the diagnostic bone marrow biopsy is performed. This may help identify AML patients who could benefit from receiving an IDO inhibitor along with standard therapy.
Researchers are currently conducting a phase 1/2 trial of the IDO inhibitor indoximod in combination with idarubicin and cytarabine in patients with newly diagnosed AML (NCT02835729).
Thoughts, emotions linked to opioid use in SCD
Results of a small study suggest that negative thoughts and emotions may increase opioid use in patients with sickle cell disease (SCD).
Researchers analyzed data from daily electronic patient diaries and found that patients were more likely to use short-acting opioids both when they experienced increased pain and “catastrophic” thoughts about that pain.
In fact, pain catastrophizing led to an increased use of short-acting opioids even when patients reported low levels of pain.
In addition, patients were more likely to use long-acting opioids when they experienced negative emotions.
The researchers noted that this study wasn’t designed to show that negative emotions or thinking cause an increase in opioid use. It was only designed to determine if there was an association.
Patrick Finan, PhD, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues described this study in The Journal of Pain.
The researchers enrolled 85 adults with SCD in this study. Patients were asked to fill out electronic diaries on a handheld personal computer every evening for 90 days.
The final analysis included only 45 patients, as these were the subjects who filled out the diary more than 25% of the time and had taken opioid pills at least once during the study period.
The patients had an average age of 37, and 71% were female. Most (93%) were African American, and 7% were classified as “other” or did not report their race.
At the start of the study, the patients reported on the dosage and type of opioid pill they were prescribed for long-acting and short-acting use. The daily diary collected data on the number of long-acting and short-acting opioid pills taken per day.
Patients rated their daily pain level on a scale of 0 to 10, with 0 being no pain and 10 being the worst pain imaginable.
Patients also rated positive emotions—including happy, calm, and cheerful—and negative emotions—including lonely, sad, anxious, and tired—on a scale of 0 to 10, with 0 being no emotion and 10 being the most intense emotion. The scores were converted to a 0-to-100 scale for the data analysis.
Separately, the researchers measured negative thinking using a Pain Catastrophizing Scale to rate “rumination,” or focus on pain, helplessness, and magnification of a current pain situation.
Results
Negative emotions were significantly associated with increased levels of long-acting opioids (P=0.001). The opioid dosage increased by 3.4 morphine milligram equivalents for every 10-point increase in negative emotions.
On the other hand, patients’ daily pain level, positive emotions, and negative thinking through catastrophizing did not significantly affect the amount of long-acting opioids taken.
“When someone is prescribed a daily, long-acting opioid, it is typically supposed to be at a fixed dose, and their pain level or emotions shouldn’t dictate whether they take more of this prescription or not,” Dr Finan said.
“Although we can’t prove misuse of the medication in our study, these data suggest that physicians and patients should clearly communicate about how patients should be taking their daily, long-acting opioids in order to minimize the potential for misuse.”
The researchers also found a significant association with short-acting opioid use and daily pain levels (P=0.006) as well as negative thinking by catastrophizing (P<0.001).
For every 10-point increase on the pain scale, the amount of short-acting opioids increased by 1.8 morphine milligram equivalents, and for every 10-point increase on the catastrophizing scale, pain medicine dosage increased by 2.5 morphine milligram equivalents.
Positive and negative emotions had no significant effect on the use of short-acting opioids.
“When pain was reported as low, sickle cell disease patients reported higher opioid use if they catastrophized, or focused their thinking on their pain, than if they didn’t,” Dr Finan said. “When pain levels were higher, negative thinking played less of a role in influencing opioid use.”
Dr Finan cautioned that studies such as this have some weaknesses, including the fact that self-reports are always uncertain, and the study only included 1 time point per day, although a person’s mood may fluctuate throughout the day based on life events and experiences.
For future studies, Dr Finan wants to use smartphone technology that can assess moods randomly throughout the day.
“Once we have a more intensive study to track mood variations throughout the day,” Dr Finan said, “then we can determine when it will be appropriate to send messages through text to intervene and affect patient behavior.”
Results of a small study suggest that negative thoughts and emotions may increase opioid use in patients with sickle cell disease (SCD).
Researchers analyzed data from daily electronic patient diaries and found that patients were more likely to use short-acting opioids both when they experienced increased pain and “catastrophic” thoughts about that pain.
In fact, pain catastrophizing led to an increased use of short-acting opioids even when patients reported low levels of pain.
In addition, patients were more likely to use long-acting opioids when they experienced negative emotions.
The researchers noted that this study wasn’t designed to show that negative emotions or thinking cause an increase in opioid use. It was only designed to determine if there was an association.
Patrick Finan, PhD, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues described this study in The Journal of Pain.
The researchers enrolled 85 adults with SCD in this study. Patients were asked to fill out electronic diaries on a handheld personal computer every evening for 90 days.
The final analysis included only 45 patients, as these were the subjects who filled out the diary more than 25% of the time and had taken opioid pills at least once during the study period.
The patients had an average age of 37, and 71% were female. Most (93%) were African American, and 7% were classified as “other” or did not report their race.
At the start of the study, the patients reported on the dosage and type of opioid pill they were prescribed for long-acting and short-acting use. The daily diary collected data on the number of long-acting and short-acting opioid pills taken per day.
Patients rated their daily pain level on a scale of 0 to 10, with 0 being no pain and 10 being the worst pain imaginable.
Patients also rated positive emotions—including happy, calm, and cheerful—and negative emotions—including lonely, sad, anxious, and tired—on a scale of 0 to 10, with 0 being no emotion and 10 being the most intense emotion. The scores were converted to a 0-to-100 scale for the data analysis.
Separately, the researchers measured negative thinking using a Pain Catastrophizing Scale to rate “rumination,” or focus on pain, helplessness, and magnification of a current pain situation.
Results
Negative emotions were significantly associated with increased levels of long-acting opioids (P=0.001). The opioid dosage increased by 3.4 morphine milligram equivalents for every 10-point increase in negative emotions.
On the other hand, patients’ daily pain level, positive emotions, and negative thinking through catastrophizing did not significantly affect the amount of long-acting opioids taken.
“When someone is prescribed a daily, long-acting opioid, it is typically supposed to be at a fixed dose, and their pain level or emotions shouldn’t dictate whether they take more of this prescription or not,” Dr Finan said.
“Although we can’t prove misuse of the medication in our study, these data suggest that physicians and patients should clearly communicate about how patients should be taking their daily, long-acting opioids in order to minimize the potential for misuse.”
The researchers also found a significant association with short-acting opioid use and daily pain levels (P=0.006) as well as negative thinking by catastrophizing (P<0.001).
For every 10-point increase on the pain scale, the amount of short-acting opioids increased by 1.8 morphine milligram equivalents, and for every 10-point increase on the catastrophizing scale, pain medicine dosage increased by 2.5 morphine milligram equivalents.
Positive and negative emotions had no significant effect on the use of short-acting opioids.
“When pain was reported as low, sickle cell disease patients reported higher opioid use if they catastrophized, or focused their thinking on their pain, than if they didn’t,” Dr Finan said. “When pain levels were higher, negative thinking played less of a role in influencing opioid use.”
Dr Finan cautioned that studies such as this have some weaknesses, including the fact that self-reports are always uncertain, and the study only included 1 time point per day, although a person’s mood may fluctuate throughout the day based on life events and experiences.
For future studies, Dr Finan wants to use smartphone technology that can assess moods randomly throughout the day.
“Once we have a more intensive study to track mood variations throughout the day,” Dr Finan said, “then we can determine when it will be appropriate to send messages through text to intervene and affect patient behavior.”
Results of a small study suggest that negative thoughts and emotions may increase opioid use in patients with sickle cell disease (SCD).
Researchers analyzed data from daily electronic patient diaries and found that patients were more likely to use short-acting opioids both when they experienced increased pain and “catastrophic” thoughts about that pain.
In fact, pain catastrophizing led to an increased use of short-acting opioids even when patients reported low levels of pain.
In addition, patients were more likely to use long-acting opioids when they experienced negative emotions.
The researchers noted that this study wasn’t designed to show that negative emotions or thinking cause an increase in opioid use. It was only designed to determine if there was an association.
Patrick Finan, PhD, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues described this study in The Journal of Pain.
The researchers enrolled 85 adults with SCD in this study. Patients were asked to fill out electronic diaries on a handheld personal computer every evening for 90 days.
The final analysis included only 45 patients, as these were the subjects who filled out the diary more than 25% of the time and had taken opioid pills at least once during the study period.
The patients had an average age of 37, and 71% were female. Most (93%) were African American, and 7% were classified as “other” or did not report their race.
At the start of the study, the patients reported on the dosage and type of opioid pill they were prescribed for long-acting and short-acting use. The daily diary collected data on the number of long-acting and short-acting opioid pills taken per day.
Patients rated their daily pain level on a scale of 0 to 10, with 0 being no pain and 10 being the worst pain imaginable.
Patients also rated positive emotions—including happy, calm, and cheerful—and negative emotions—including lonely, sad, anxious, and tired—on a scale of 0 to 10, with 0 being no emotion and 10 being the most intense emotion. The scores were converted to a 0-to-100 scale for the data analysis.
Separately, the researchers measured negative thinking using a Pain Catastrophizing Scale to rate “rumination,” or focus on pain, helplessness, and magnification of a current pain situation.
Results
Negative emotions were significantly associated with increased levels of long-acting opioids (P=0.001). The opioid dosage increased by 3.4 morphine milligram equivalents for every 10-point increase in negative emotions.
On the other hand, patients’ daily pain level, positive emotions, and negative thinking through catastrophizing did not significantly affect the amount of long-acting opioids taken.
“When someone is prescribed a daily, long-acting opioid, it is typically supposed to be at a fixed dose, and their pain level or emotions shouldn’t dictate whether they take more of this prescription or not,” Dr Finan said.
“Although we can’t prove misuse of the medication in our study, these data suggest that physicians and patients should clearly communicate about how patients should be taking their daily, long-acting opioids in order to minimize the potential for misuse.”
The researchers also found a significant association with short-acting opioid use and daily pain levels (P=0.006) as well as negative thinking by catastrophizing (P<0.001).
For every 10-point increase on the pain scale, the amount of short-acting opioids increased by 1.8 morphine milligram equivalents, and for every 10-point increase on the catastrophizing scale, pain medicine dosage increased by 2.5 morphine milligram equivalents.
Positive and negative emotions had no significant effect on the use of short-acting opioids.
“When pain was reported as low, sickle cell disease patients reported higher opioid use if they catastrophized, or focused their thinking on their pain, than if they didn’t,” Dr Finan said. “When pain levels were higher, negative thinking played less of a role in influencing opioid use.”
Dr Finan cautioned that studies such as this have some weaknesses, including the fact that self-reports are always uncertain, and the study only included 1 time point per day, although a person’s mood may fluctuate throughout the day based on life events and experiences.
For future studies, Dr Finan wants to use smartphone technology that can assess moods randomly throughout the day.
“Once we have a more intensive study to track mood variations throughout the day,” Dr Finan said, “then we can determine when it will be appropriate to send messages through text to intervene and affect patient behavior.”
Authors’ contributions to studies often unclear
Although many scientific journals try to provide details about authors’ contributions to a publication by requiring explicit statements, contribution statements get much less attention than authorship order, according to research published in Science Advances.
Researchers surveyed more than 6000 corresponding authors of studies published in recent years and found they consider contribution statements helpful for understanding the specific skills individual authors bring to a study.
However, the respondents said they still use author order for deciphering which authors did how much of the work and deserve most of the credit.
“The lack of uniformity and detail in contribution statements leaves open the door for varied interpretations, which could be why only a minority of respondents found them more useful than author order,” said Henry Sauermann, PhD, of ESMT Berlin in Germany.
Dr Sauermann and his colleagues also examined the relationship between author order and contribution statements on more than 12,000 published articles.
The contribution statements studied did include information about the types of work contributed by each author. However, multiple authors could be listed under the same contributions, and the statements had little information about the level of effort for each author.
The statements also said little about how important a particular contribution was for project success.
Still, Dr Sauermann and his colleagues noted that author order has its own problems.
“When we talked to scientists, many think that there are certain norms, and they know how to interpret author order,” Dr Sauermann said. “But when you really push, it’s not clear at all, at least not at the level of detail we need.”
That’s further complicated by the fact that conventions of author order vary depending on the research field.
This work also revealed a difference of opinion between junior and senior researchers, with the former caring more strongly about contribution statements and how they are discussed and crafted.
“When we read open-ended responses to our survey questions, we got the impression of a really divided community,” Dr Sauermann said. “Some believe that forcing more detail in contribution statements is great, and some are concerned that it could really hurt teamwork and collaboration. It’s not that everyone is lukewarm; many really care.”
That level of interest could pave the way for more discussion, which is something Dr Sauermann said is ultimately needed for the scientific and research community to move forward and add more clarity to the process.
“This is not going to get any easier,” Dr Sauermann said. “It’s going to get harder as how we perform research changes and as teams get bigger and more diverse.”
Although many scientific journals try to provide details about authors’ contributions to a publication by requiring explicit statements, contribution statements get much less attention than authorship order, according to research published in Science Advances.
Researchers surveyed more than 6000 corresponding authors of studies published in recent years and found they consider contribution statements helpful for understanding the specific skills individual authors bring to a study.
However, the respondents said they still use author order for deciphering which authors did how much of the work and deserve most of the credit.
“The lack of uniformity and detail in contribution statements leaves open the door for varied interpretations, which could be why only a minority of respondents found them more useful than author order,” said Henry Sauermann, PhD, of ESMT Berlin in Germany.
Dr Sauermann and his colleagues also examined the relationship between author order and contribution statements on more than 12,000 published articles.
The contribution statements studied did include information about the types of work contributed by each author. However, multiple authors could be listed under the same contributions, and the statements had little information about the level of effort for each author.
The statements also said little about how important a particular contribution was for project success.
Still, Dr Sauermann and his colleagues noted that author order has its own problems.
“When we talked to scientists, many think that there are certain norms, and they know how to interpret author order,” Dr Sauermann said. “But when you really push, it’s not clear at all, at least not at the level of detail we need.”
That’s further complicated by the fact that conventions of author order vary depending on the research field.
This work also revealed a difference of opinion between junior and senior researchers, with the former caring more strongly about contribution statements and how they are discussed and crafted.
“When we read open-ended responses to our survey questions, we got the impression of a really divided community,” Dr Sauermann said. “Some believe that forcing more detail in contribution statements is great, and some are concerned that it could really hurt teamwork and collaboration. It’s not that everyone is lukewarm; many really care.”
That level of interest could pave the way for more discussion, which is something Dr Sauermann said is ultimately needed for the scientific and research community to move forward and add more clarity to the process.
“This is not going to get any easier,” Dr Sauermann said. “It’s going to get harder as how we perform research changes and as teams get bigger and more diverse.”
Although many scientific journals try to provide details about authors’ contributions to a publication by requiring explicit statements, contribution statements get much less attention than authorship order, according to research published in Science Advances.
Researchers surveyed more than 6000 corresponding authors of studies published in recent years and found they consider contribution statements helpful for understanding the specific skills individual authors bring to a study.
However, the respondents said they still use author order for deciphering which authors did how much of the work and deserve most of the credit.
“The lack of uniformity and detail in contribution statements leaves open the door for varied interpretations, which could be why only a minority of respondents found them more useful than author order,” said Henry Sauermann, PhD, of ESMT Berlin in Germany.
Dr Sauermann and his colleagues also examined the relationship between author order and contribution statements on more than 12,000 published articles.
The contribution statements studied did include information about the types of work contributed by each author. However, multiple authors could be listed under the same contributions, and the statements had little information about the level of effort for each author.
The statements also said little about how important a particular contribution was for project success.
Still, Dr Sauermann and his colleagues noted that author order has its own problems.
“When we talked to scientists, many think that there are certain norms, and they know how to interpret author order,” Dr Sauermann said. “But when you really push, it’s not clear at all, at least not at the level of detail we need.”
That’s further complicated by the fact that conventions of author order vary depending on the research field.
This work also revealed a difference of opinion between junior and senior researchers, with the former caring more strongly about contribution statements and how they are discussed and crafted.
“When we read open-ended responses to our survey questions, we got the impression of a really divided community,” Dr Sauermann said. “Some believe that forcing more detail in contribution statements is great, and some are concerned that it could really hurt teamwork and collaboration. It’s not that everyone is lukewarm; many really care.”
That level of interest could pave the way for more discussion, which is something Dr Sauermann said is ultimately needed for the scientific and research community to move forward and add more clarity to the process.
“This is not going to get any easier,” Dr Sauermann said. “It’s going to get harder as how we perform research changes and as teams get bigger and more diverse.”
Team identifies genetic differences between MM patients
Researchers say they have identified significant genetic differences between African-American patients with multiple myeloma (MM) and Caucasian patients with the disease.
For example, the researchers found that African Americans were more likely to have mutations in BCL7A, BRWD3, and AUTS2, but Caucasians were more likely to have mutations in IRF4 and TP53.
“A cancer therapy that targets TP53 would not be as effective for African Americans with multiple myeloma as it would be for a white population because doctors would be trying to fix the wrong mutated gene,” said Zarko Manojlovic, PhD, of the University of Southern California in Los Angeles.
Dr Manojlovic and his colleagues conducted this research and detailed the results in PLOS Genetics.
The researchers analyzed genetic sequencing data and clinical data from 718 MM patients participating in the MMRF CoMMpass Study.
Race was reported by the patients, but the researchers also used the genetic data to determine that 127 patients were of African descent and 591 were of European descent. The researchers noted that the mean European admixture among self-reported African Americans was 31% (range; 11%-67.8%). And the mean west-African admixture among self-reported Caucasians was 0.1% (range; 0-34.3).
The African-American patients were significantly more likely than the Caucasians to have early onset MM (at ages 40-49)—11% and 4.6%, respectively (P=0.004). And Caucasians were significantly more likely than African Americans to have late-onset MM (at ages 70-79)—22% and 14%, respectively (P=0.04).
There was no significant difference in overall survival based on race, age of onset, or MM karyotype in this population.
Mutations in the following genes occurred at significantly higher frequencies in African-American patients than in Caucasians: RYR1, RPL10, PTCHD3, BCL7A, SPEF2, MYH13, ABI3BP, BRWD3, GRM7, AUTS2, PARP4, PLD1, ANKRD26, DDX17, and STXBP4.
On the other hand, Caucasians had a significantly higher frequency of mutations in IRF4 and TP53. In fact, there was a TP53 somatic mutation frequency of 6.3% in Caucasians and 1.6% in African Americans (P=0.035).
“One of the most surprising discoveries from this large cohort is that cancers from patients of European descent were 6 times more likely than their African-descent counterparts to have mutations in TP53, a known tumor suppressor gene,” Dr Manojlovic said.
“Biologically speaking, higher mutation rates in this gene should lead to overall lower survival rates among patients of European descent, but that does not correlate with what we see in clinical outcomes. Going forward, we hope to functionally validate these results for more insight into the underlying biology.”
“We in the cancer genomics community have a responsibility to ensure that our studies represent true population diversity so we can understand the role of ancestry and biology in health outcomes,” added study author John D. Carpten, PhD, of the University of Southern California.
“The new candidate myeloma genes we identified in the African-American population may have been overlooked because of the lack of diversity in previous genomic efforts. There are clearly molecular differences between African-American and Caucasian multiple myeloma cases, and it will be critical to pursue these observations to better improve clinical management of the disease for all patients.”
Researchers say they have identified significant genetic differences between African-American patients with multiple myeloma (MM) and Caucasian patients with the disease.
For example, the researchers found that African Americans were more likely to have mutations in BCL7A, BRWD3, and AUTS2, but Caucasians were more likely to have mutations in IRF4 and TP53.
“A cancer therapy that targets TP53 would not be as effective for African Americans with multiple myeloma as it would be for a white population because doctors would be trying to fix the wrong mutated gene,” said Zarko Manojlovic, PhD, of the University of Southern California in Los Angeles.
Dr Manojlovic and his colleagues conducted this research and detailed the results in PLOS Genetics.
The researchers analyzed genetic sequencing data and clinical data from 718 MM patients participating in the MMRF CoMMpass Study.
Race was reported by the patients, but the researchers also used the genetic data to determine that 127 patients were of African descent and 591 were of European descent. The researchers noted that the mean European admixture among self-reported African Americans was 31% (range; 11%-67.8%). And the mean west-African admixture among self-reported Caucasians was 0.1% (range; 0-34.3).
The African-American patients were significantly more likely than the Caucasians to have early onset MM (at ages 40-49)—11% and 4.6%, respectively (P=0.004). And Caucasians were significantly more likely than African Americans to have late-onset MM (at ages 70-79)—22% and 14%, respectively (P=0.04).
There was no significant difference in overall survival based on race, age of onset, or MM karyotype in this population.
Mutations in the following genes occurred at significantly higher frequencies in African-American patients than in Caucasians: RYR1, RPL10, PTCHD3, BCL7A, SPEF2, MYH13, ABI3BP, BRWD3, GRM7, AUTS2, PARP4, PLD1, ANKRD26, DDX17, and STXBP4.
On the other hand, Caucasians had a significantly higher frequency of mutations in IRF4 and TP53. In fact, there was a TP53 somatic mutation frequency of 6.3% in Caucasians and 1.6% in African Americans (P=0.035).
“One of the most surprising discoveries from this large cohort is that cancers from patients of European descent were 6 times more likely than their African-descent counterparts to have mutations in TP53, a known tumor suppressor gene,” Dr Manojlovic said.
“Biologically speaking, higher mutation rates in this gene should lead to overall lower survival rates among patients of European descent, but that does not correlate with what we see in clinical outcomes. Going forward, we hope to functionally validate these results for more insight into the underlying biology.”
“We in the cancer genomics community have a responsibility to ensure that our studies represent true population diversity so we can understand the role of ancestry and biology in health outcomes,” added study author John D. Carpten, PhD, of the University of Southern California.
“The new candidate myeloma genes we identified in the African-American population may have been overlooked because of the lack of diversity in previous genomic efforts. There are clearly molecular differences between African-American and Caucasian multiple myeloma cases, and it will be critical to pursue these observations to better improve clinical management of the disease for all patients.”
Researchers say they have identified significant genetic differences between African-American patients with multiple myeloma (MM) and Caucasian patients with the disease.
For example, the researchers found that African Americans were more likely to have mutations in BCL7A, BRWD3, and AUTS2, but Caucasians were more likely to have mutations in IRF4 and TP53.
“A cancer therapy that targets TP53 would not be as effective for African Americans with multiple myeloma as it would be for a white population because doctors would be trying to fix the wrong mutated gene,” said Zarko Manojlovic, PhD, of the University of Southern California in Los Angeles.
Dr Manojlovic and his colleagues conducted this research and detailed the results in PLOS Genetics.
The researchers analyzed genetic sequencing data and clinical data from 718 MM patients participating in the MMRF CoMMpass Study.
Race was reported by the patients, but the researchers also used the genetic data to determine that 127 patients were of African descent and 591 were of European descent. The researchers noted that the mean European admixture among self-reported African Americans was 31% (range; 11%-67.8%). And the mean west-African admixture among self-reported Caucasians was 0.1% (range; 0-34.3).
The African-American patients were significantly more likely than the Caucasians to have early onset MM (at ages 40-49)—11% and 4.6%, respectively (P=0.004). And Caucasians were significantly more likely than African Americans to have late-onset MM (at ages 70-79)—22% and 14%, respectively (P=0.04).
There was no significant difference in overall survival based on race, age of onset, or MM karyotype in this population.
Mutations in the following genes occurred at significantly higher frequencies in African-American patients than in Caucasians: RYR1, RPL10, PTCHD3, BCL7A, SPEF2, MYH13, ABI3BP, BRWD3, GRM7, AUTS2, PARP4, PLD1, ANKRD26, DDX17, and STXBP4.
On the other hand, Caucasians had a significantly higher frequency of mutations in IRF4 and TP53. In fact, there was a TP53 somatic mutation frequency of 6.3% in Caucasians and 1.6% in African Americans (P=0.035).
“One of the most surprising discoveries from this large cohort is that cancers from patients of European descent were 6 times more likely than their African-descent counterparts to have mutations in TP53, a known tumor suppressor gene,” Dr Manojlovic said.
“Biologically speaking, higher mutation rates in this gene should lead to overall lower survival rates among patients of European descent, but that does not correlate with what we see in clinical outcomes. Going forward, we hope to functionally validate these results for more insight into the underlying biology.”
“We in the cancer genomics community have a responsibility to ensure that our studies represent true population diversity so we can understand the role of ancestry and biology in health outcomes,” added study author John D. Carpten, PhD, of the University of Southern California.
“The new candidate myeloma genes we identified in the African-American population may have been overlooked because of the lack of diversity in previous genomic efforts. There are clearly molecular differences between African-American and Caucasian multiple myeloma cases, and it will be critical to pursue these observations to better improve clinical management of the disease for all patients.”
How CLL patients weigh treatment efficacy, safety, and cost
New research suggests patients with chronic lymphocytic leukemia (CLL) are willing to trade treatment efficacy for a reduced risk of side effects, but the cost of treatment may trump other factors.
The patients studied placed the highest value on treatments that deliver the longest progression-free survival (PFS), but the patients were also willing to swap some efficacy for a reduced risk of serious adverse events (AEs).
Study results also indicated that factoring out-of-pocket costs into the decision-making process can significantly influence a patient’s choice of treatment.
Carol Mansfield, PhD, of RTI Health Solutions in Research Triangle Park, North Carolina, and her colleagues conducted this study and reported the results in Blood Advances. The study was supported by funding from Genentech, Inc., to RTI Health Solutions.
The researchers surveyed 384 patients with CLL. Patients were asked to choose between hypothetical treatment options, each of which was defined by 5 variable attributes—PFS, mode of administration, typical severity of diarrhea, chance of serious infection, and chance of organ damage.
The attribute patients ranked highest was a change in PFS from 10 months to 60 months. This was followed by a change in infection risk from 30% to 0%, a change in the risk of organ damage from 8% to 0%, a change in diarrhea from severe to none, and a change in the mode of administration from intravenous to oral.
On average, a gain in PFS of 35.9 months was needed for patients to accept a 30% risk of serious infection. A gain in PFS of 26.3 months was needed for patients to accept an 8% risk of organ damage.
A gain in PFS of 21.6 months was needed for patients to accept severe diarrhea. And a gain in PFS of 3.5 months was needed for patients to accept the change from a daily pill to intravenous administration for 6 months.
There were no significant differences in preferences among treatment-naïve patients, first-line patients, and relapsed/refractory patients.
Impact of cost
When the researchers conducted a supplemental cost analysis, they found that out-of-pocket cost had a substantial impact on treatment choice.
The cost analysis included 2 treatments—medicines A and B. Based on the prior analysis, the researchers predicted that 91% of patients would choose medicine B if cost were not a concern because B offered longer PFS than A.
“We used the results from the discrete-choice experiment to forecast the probability that a respondent would pick each hypothetical drug without any mention of cost and then compared that to the choices people made when out-of-pocket costs for these medicines were included,” Dr Mansfield explained.
Patients were asked to choose between medicines A and B under 2 circumstances in which B cost more than A.
When medicine B had a monthly out-of-pocket cost that was $75 more than medicine A, 50% of patients chose medicine A.
When medicine B had a monthly out-of-pocket cost that was $400 more than medicine A, 74% of patients chose medicine A.
“Cost is clearly something that has an impact,” Dr Mansfield said. “When patients get prescribed something they can’t afford, they have to make very difficult choices.”
Dr Mansfield and her colleagues believe their findings will help doctors and patients focus on treatments that account for a patient’s unique circumstances and goals.
“Patients don’t always know that they could be making these tradeoffs,” Dr Mansfield said. “We hope that our findings can help doctors to have frank discussions with their patients about the differences between treatments and how these might affect their lives.”
New research suggests patients with chronic lymphocytic leukemia (CLL) are willing to trade treatment efficacy for a reduced risk of side effects, but the cost of treatment may trump other factors.
The patients studied placed the highest value on treatments that deliver the longest progression-free survival (PFS), but the patients were also willing to swap some efficacy for a reduced risk of serious adverse events (AEs).
Study results also indicated that factoring out-of-pocket costs into the decision-making process can significantly influence a patient’s choice of treatment.
Carol Mansfield, PhD, of RTI Health Solutions in Research Triangle Park, North Carolina, and her colleagues conducted this study and reported the results in Blood Advances. The study was supported by funding from Genentech, Inc., to RTI Health Solutions.
The researchers surveyed 384 patients with CLL. Patients were asked to choose between hypothetical treatment options, each of which was defined by 5 variable attributes—PFS, mode of administration, typical severity of diarrhea, chance of serious infection, and chance of organ damage.
The attribute patients ranked highest was a change in PFS from 10 months to 60 months. This was followed by a change in infection risk from 30% to 0%, a change in the risk of organ damage from 8% to 0%, a change in diarrhea from severe to none, and a change in the mode of administration from intravenous to oral.
On average, a gain in PFS of 35.9 months was needed for patients to accept a 30% risk of serious infection. A gain in PFS of 26.3 months was needed for patients to accept an 8% risk of organ damage.
A gain in PFS of 21.6 months was needed for patients to accept severe diarrhea. And a gain in PFS of 3.5 months was needed for patients to accept the change from a daily pill to intravenous administration for 6 months.
There were no significant differences in preferences among treatment-naïve patients, first-line patients, and relapsed/refractory patients.
Impact of cost
When the researchers conducted a supplemental cost analysis, they found that out-of-pocket cost had a substantial impact on treatment choice.
The cost analysis included 2 treatments—medicines A and B. Based on the prior analysis, the researchers predicted that 91% of patients would choose medicine B if cost were not a concern because B offered longer PFS than A.
“We used the results from the discrete-choice experiment to forecast the probability that a respondent would pick each hypothetical drug without any mention of cost and then compared that to the choices people made when out-of-pocket costs for these medicines were included,” Dr Mansfield explained.
Patients were asked to choose between medicines A and B under 2 circumstances in which B cost more than A.
When medicine B had a monthly out-of-pocket cost that was $75 more than medicine A, 50% of patients chose medicine A.
When medicine B had a monthly out-of-pocket cost that was $400 more than medicine A, 74% of patients chose medicine A.
“Cost is clearly something that has an impact,” Dr Mansfield said. “When patients get prescribed something they can’t afford, they have to make very difficult choices.”
Dr Mansfield and her colleagues believe their findings will help doctors and patients focus on treatments that account for a patient’s unique circumstances and goals.
“Patients don’t always know that they could be making these tradeoffs,” Dr Mansfield said. “We hope that our findings can help doctors to have frank discussions with their patients about the differences between treatments and how these might affect their lives.”
New research suggests patients with chronic lymphocytic leukemia (CLL) are willing to trade treatment efficacy for a reduced risk of side effects, but the cost of treatment may trump other factors.
The patients studied placed the highest value on treatments that deliver the longest progression-free survival (PFS), but the patients were also willing to swap some efficacy for a reduced risk of serious adverse events (AEs).
Study results also indicated that factoring out-of-pocket costs into the decision-making process can significantly influence a patient’s choice of treatment.
Carol Mansfield, PhD, of RTI Health Solutions in Research Triangle Park, North Carolina, and her colleagues conducted this study and reported the results in Blood Advances. The study was supported by funding from Genentech, Inc., to RTI Health Solutions.
The researchers surveyed 384 patients with CLL. Patients were asked to choose between hypothetical treatment options, each of which was defined by 5 variable attributes—PFS, mode of administration, typical severity of diarrhea, chance of serious infection, and chance of organ damage.
The attribute patients ranked highest was a change in PFS from 10 months to 60 months. This was followed by a change in infection risk from 30% to 0%, a change in the risk of organ damage from 8% to 0%, a change in diarrhea from severe to none, and a change in the mode of administration from intravenous to oral.
On average, a gain in PFS of 35.9 months was needed for patients to accept a 30% risk of serious infection. A gain in PFS of 26.3 months was needed for patients to accept an 8% risk of organ damage.
A gain in PFS of 21.6 months was needed for patients to accept severe diarrhea. And a gain in PFS of 3.5 months was needed for patients to accept the change from a daily pill to intravenous administration for 6 months.
There were no significant differences in preferences among treatment-naïve patients, first-line patients, and relapsed/refractory patients.
Impact of cost
When the researchers conducted a supplemental cost analysis, they found that out-of-pocket cost had a substantial impact on treatment choice.
The cost analysis included 2 treatments—medicines A and B. Based on the prior analysis, the researchers predicted that 91% of patients would choose medicine B if cost were not a concern because B offered longer PFS than A.
“We used the results from the discrete-choice experiment to forecast the probability that a respondent would pick each hypothetical drug without any mention of cost and then compared that to the choices people made when out-of-pocket costs for these medicines were included,” Dr Mansfield explained.
Patients were asked to choose between medicines A and B under 2 circumstances in which B cost more than A.
When medicine B had a monthly out-of-pocket cost that was $75 more than medicine A, 50% of patients chose medicine A.
When medicine B had a monthly out-of-pocket cost that was $400 more than medicine A, 74% of patients chose medicine A.
“Cost is clearly something that has an impact,” Dr Mansfield said. “When patients get prescribed something they can’t afford, they have to make very difficult choices.”
Dr Mansfield and her colleagues believe their findings will help doctors and patients focus on treatments that account for a patient’s unique circumstances and goals.
“Patients don’t always know that they could be making these tradeoffs,” Dr Mansfield said. “We hope that our findings can help doctors to have frank discussions with their patients about the differences between treatments and how these might affect their lives.”
Review suggests low incidence of BIA-ALCL in Canada
Results of a safety review suggest there is a low incidence of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) in Canada.
Health Canada undertook the review because of an increase in reporting of BIA-ALCL internationally.
The review showed that 5 confirmed cases of BIA-ALCL have been reported by Canadian manufacturers in the last 10 years.
This is equal to 1 case of BIA-ALCL per 77,190 implants sold, or 0.0013%.
However, Health Canada acknowledges that some cases may not have been reported to the manufacturers or Health Canada.
Available data suggest that BIA-ALCL is more frequently reported with textured surface implants than smooth surface implants. Textured surface implants account for a quarter of all breast implants sold in Canada.
Four of the 5 reported Canadian cases of BIA-ALCL involved textured implants. The surface type was not reported in the remaining case.
The rate of occurrence of BIA‑ALCL per textured implant sold in Canada is 1 case per 24,177 or 0.0041%.
As a result of its safety review, Health Canada is working with manufacturers to update the safety information on the product labeling for all breast implants.
The agency is also communicating this safety information to Canadians through the Recalls and Safety Alerts database on the Healthy Canadians website.
Health Canada continues to monitor the safety profile of breast implants through its post-market surveillance program.
The agency will also monitor cases of BIA-ALCL through an annual follow-up with manufacturers of breast implants.
Health Canada is recommending that healthcare professionals learn about the signs, symptoms, and testing steps to recognize and diagnose BIA‑ALCL.
In addition, healthcare professionals in Canada should report incidents of BIA-ALCL to Health Canada. These reports should include specific details, such as symptoms, how BIA-ALCL was discovered, the age of the patient at implantation, prior implant history, the age of the patient at discovery, tests conducted to diagnose BIA-ALCL, staging information, the course of therapy, and clinical outcomes.
Reports can be made by calling Health Canada at 1-866-234-2345. Alternatively, visit Health Canada’s webpage on Adverse Reaction Reporting for information on how to report online, by mail, or by fax.
Results of a safety review suggest there is a low incidence of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) in Canada.
Health Canada undertook the review because of an increase in reporting of BIA-ALCL internationally.
The review showed that 5 confirmed cases of BIA-ALCL have been reported by Canadian manufacturers in the last 10 years.
This is equal to 1 case of BIA-ALCL per 77,190 implants sold, or 0.0013%.
However, Health Canada acknowledges that some cases may not have been reported to the manufacturers or Health Canada.
Available data suggest that BIA-ALCL is more frequently reported with textured surface implants than smooth surface implants. Textured surface implants account for a quarter of all breast implants sold in Canada.
Four of the 5 reported Canadian cases of BIA-ALCL involved textured implants. The surface type was not reported in the remaining case.
The rate of occurrence of BIA‑ALCL per textured implant sold in Canada is 1 case per 24,177 or 0.0041%.
As a result of its safety review, Health Canada is working with manufacturers to update the safety information on the product labeling for all breast implants.
The agency is also communicating this safety information to Canadians through the Recalls and Safety Alerts database on the Healthy Canadians website.
Health Canada continues to monitor the safety profile of breast implants through its post-market surveillance program.
The agency will also monitor cases of BIA-ALCL through an annual follow-up with manufacturers of breast implants.
Health Canada is recommending that healthcare professionals learn about the signs, symptoms, and testing steps to recognize and diagnose BIA‑ALCL.
In addition, healthcare professionals in Canada should report incidents of BIA-ALCL to Health Canada. These reports should include specific details, such as symptoms, how BIA-ALCL was discovered, the age of the patient at implantation, prior implant history, the age of the patient at discovery, tests conducted to diagnose BIA-ALCL, staging information, the course of therapy, and clinical outcomes.
Reports can be made by calling Health Canada at 1-866-234-2345. Alternatively, visit Health Canada’s webpage on Adverse Reaction Reporting for information on how to report online, by mail, or by fax.
Results of a safety review suggest there is a low incidence of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) in Canada.
Health Canada undertook the review because of an increase in reporting of BIA-ALCL internationally.
The review showed that 5 confirmed cases of BIA-ALCL have been reported by Canadian manufacturers in the last 10 years.
This is equal to 1 case of BIA-ALCL per 77,190 implants sold, or 0.0013%.
However, Health Canada acknowledges that some cases may not have been reported to the manufacturers or Health Canada.
Available data suggest that BIA-ALCL is more frequently reported with textured surface implants than smooth surface implants. Textured surface implants account for a quarter of all breast implants sold in Canada.
Four of the 5 reported Canadian cases of BIA-ALCL involved textured implants. The surface type was not reported in the remaining case.
The rate of occurrence of BIA‑ALCL per textured implant sold in Canada is 1 case per 24,177 or 0.0041%.
As a result of its safety review, Health Canada is working with manufacturers to update the safety information on the product labeling for all breast implants.
The agency is also communicating this safety information to Canadians through the Recalls and Safety Alerts database on the Healthy Canadians website.
Health Canada continues to monitor the safety profile of breast implants through its post-market surveillance program.
The agency will also monitor cases of BIA-ALCL through an annual follow-up with manufacturers of breast implants.
Health Canada is recommending that healthcare professionals learn about the signs, symptoms, and testing steps to recognize and diagnose BIA‑ALCL.
In addition, healthcare professionals in Canada should report incidents of BIA-ALCL to Health Canada. These reports should include specific details, such as symptoms, how BIA-ALCL was discovered, the age of the patient at implantation, prior implant history, the age of the patient at discovery, tests conducted to diagnose BIA-ALCL, staging information, the course of therapy, and clinical outcomes.
Reports can be made by calling Health Canada at 1-866-234-2345. Alternatively, visit Health Canada’s webpage on Adverse Reaction Reporting for information on how to report online, by mail, or by fax.
CCSs have increased risk of hypertension
A study of childhood cancer survivors (CCSs) suggests these individuals have an increased risk of developing hypertension as adults.
The CCSs studied had more than double the rate of hypertension observed in the matched general population.
Sex, age, race, and weight were all significantly associated with hypertension among CCSs, but most treatment types were not.
The exception was nephrectomy, which was associated with an increased risk of hypertension.
Todd M. Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported the results in Cancer Epidemiology, Biomarkers & Prevention.
“High blood pressure is an important modifiable risk factor that increases the risk of heart problems in everyone,” Dr Gibson said. “Research has shown that high blood pressure can have an even greater negative impact on survivors of childhood cancer who were treated with cardiotoxic therapies such as anthracyclines or chest radiation.”
To assess the prevalence of hypertension among CCSs, Dr Gibson and his colleagues examined 3016 adults who were 10-year survivors of childhood cancers. The subjects were enrolled in the St. Jude Lifetime Cohort Study, which provides ongoing medical assessments of CCSs to advance knowledge of their long-term health outcomes.
The subjects’ mean age at the initial study assessment was 32, and 52% were male. Most (83%) were non-Hispanic white, 14% were non-Hispanic black, 2% were Hispanic, and 1% were “other.”
Thirty-seven percent of subjects had leukemia, 12% had Hodgkin lymphoma, and 7% had non-Hodgkin lymphoma.
Eighty-six percent of subjects had received chemotherapy, and 59% received radiation.
Results
Subjects were considered to have hypertension if their systolic blood pressure was 140 or greater, their diastolic blood pressure was 90 or greater, or if they had been previously diagnosed with hypertension and were taking antihypertensive medication.
The prevalence of hypertension was 2.6 times higher among CCSs than expected, based on age-, sex-, race- and body mass index-specific rates in the general population.
In addition, the incidence of hypertension increased for CCSs over time. Thirteen percent of CCSs had hypertension at age 30, 37% had it at age 40, and more than 70% had it at age 50.
Dr Gibson said rates of hypertension in CCSs matched rates in the general population of people about a decade older.
The researchers identified several factors that were significantly associated with hypertension among CCSs, including:
- Male sex (odd ratio [OR], 1.38; 95% CI, 1.14–1.67)
- Non-Hispanic black race (OR, 1.66; 95% CI, 1.28–2.16)
- Older age at assessment (OR per 1 year of age, 1.10; 95% CI, 1.08–1.11)
- Being overweight (OR, 1.58; 95% CI, 1.21–2.07)
- Obesity (OR, 3.02; 95% CI, 2.34–3.88).
Exposure to any type of radiation or chemotherapy was not significantly associated with hypertension, but nephrectomy was (OR, 1.68; 95% CI, 1.11–2.53).
Dr Gibson said the lack of an association between hypertension and radiation/chemotherapy was surprising. It suggests the connection between childhood cancer survival and adult hypertension is multifactorial and worthy of future research.
In the meantime, he said, clinicians should be mindful that CCSs are more likely than the general public to develop hypertension.
“The good news is that, unlike prior cancer therapy, high blood pressure is a modifiable risk factor,” Dr Gibson noted. “Research is needed to identify effective interventions to prevent hypertension in survivors, but our results emphasize the importance of blood pressure surveillance and management.”
Dr Gibson said a limitation of this study is that it was based on blood pressure measurements taken at a single study visit. A clinical diagnosis of hypertension typically requires measurements taken at multiple intervals.
In addition, the St. Jude Lifetime Cohort is a group of CCSs who undergo frequent clinical follow-up, so its participants may have benefited from being monitored and may therefore be in better health than CCSs who have less comprehensive follow-up.
A study of childhood cancer survivors (CCSs) suggests these individuals have an increased risk of developing hypertension as adults.
The CCSs studied had more than double the rate of hypertension observed in the matched general population.
Sex, age, race, and weight were all significantly associated with hypertension among CCSs, but most treatment types were not.
The exception was nephrectomy, which was associated with an increased risk of hypertension.
Todd M. Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported the results in Cancer Epidemiology, Biomarkers & Prevention.
“High blood pressure is an important modifiable risk factor that increases the risk of heart problems in everyone,” Dr Gibson said. “Research has shown that high blood pressure can have an even greater negative impact on survivors of childhood cancer who were treated with cardiotoxic therapies such as anthracyclines or chest radiation.”
To assess the prevalence of hypertension among CCSs, Dr Gibson and his colleagues examined 3016 adults who were 10-year survivors of childhood cancers. The subjects were enrolled in the St. Jude Lifetime Cohort Study, which provides ongoing medical assessments of CCSs to advance knowledge of their long-term health outcomes.
The subjects’ mean age at the initial study assessment was 32, and 52% were male. Most (83%) were non-Hispanic white, 14% were non-Hispanic black, 2% were Hispanic, and 1% were “other.”
Thirty-seven percent of subjects had leukemia, 12% had Hodgkin lymphoma, and 7% had non-Hodgkin lymphoma.
Eighty-six percent of subjects had received chemotherapy, and 59% received radiation.
Results
Subjects were considered to have hypertension if their systolic blood pressure was 140 or greater, their diastolic blood pressure was 90 or greater, or if they had been previously diagnosed with hypertension and were taking antihypertensive medication.
The prevalence of hypertension was 2.6 times higher among CCSs than expected, based on age-, sex-, race- and body mass index-specific rates in the general population.
In addition, the incidence of hypertension increased for CCSs over time. Thirteen percent of CCSs had hypertension at age 30, 37% had it at age 40, and more than 70% had it at age 50.
Dr Gibson said rates of hypertension in CCSs matched rates in the general population of people about a decade older.
The researchers identified several factors that were significantly associated with hypertension among CCSs, including:
- Male sex (odd ratio [OR], 1.38; 95% CI, 1.14–1.67)
- Non-Hispanic black race (OR, 1.66; 95% CI, 1.28–2.16)
- Older age at assessment (OR per 1 year of age, 1.10; 95% CI, 1.08–1.11)
- Being overweight (OR, 1.58; 95% CI, 1.21–2.07)
- Obesity (OR, 3.02; 95% CI, 2.34–3.88).
Exposure to any type of radiation or chemotherapy was not significantly associated with hypertension, but nephrectomy was (OR, 1.68; 95% CI, 1.11–2.53).
Dr Gibson said the lack of an association between hypertension and radiation/chemotherapy was surprising. It suggests the connection between childhood cancer survival and adult hypertension is multifactorial and worthy of future research.
In the meantime, he said, clinicians should be mindful that CCSs are more likely than the general public to develop hypertension.
“The good news is that, unlike prior cancer therapy, high blood pressure is a modifiable risk factor,” Dr Gibson noted. “Research is needed to identify effective interventions to prevent hypertension in survivors, but our results emphasize the importance of blood pressure surveillance and management.”
Dr Gibson said a limitation of this study is that it was based on blood pressure measurements taken at a single study visit. A clinical diagnosis of hypertension typically requires measurements taken at multiple intervals.
In addition, the St. Jude Lifetime Cohort is a group of CCSs who undergo frequent clinical follow-up, so its participants may have benefited from being monitored and may therefore be in better health than CCSs who have less comprehensive follow-up.
A study of childhood cancer survivors (CCSs) suggests these individuals have an increased risk of developing hypertension as adults.
The CCSs studied had more than double the rate of hypertension observed in the matched general population.
Sex, age, race, and weight were all significantly associated with hypertension among CCSs, but most treatment types were not.
The exception was nephrectomy, which was associated with an increased risk of hypertension.
Todd M. Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported the results in Cancer Epidemiology, Biomarkers & Prevention.
“High blood pressure is an important modifiable risk factor that increases the risk of heart problems in everyone,” Dr Gibson said. “Research has shown that high blood pressure can have an even greater negative impact on survivors of childhood cancer who were treated with cardiotoxic therapies such as anthracyclines or chest radiation.”
To assess the prevalence of hypertension among CCSs, Dr Gibson and his colleagues examined 3016 adults who were 10-year survivors of childhood cancers. The subjects were enrolled in the St. Jude Lifetime Cohort Study, which provides ongoing medical assessments of CCSs to advance knowledge of their long-term health outcomes.
The subjects’ mean age at the initial study assessment was 32, and 52% were male. Most (83%) were non-Hispanic white, 14% were non-Hispanic black, 2% were Hispanic, and 1% were “other.”
Thirty-seven percent of subjects had leukemia, 12% had Hodgkin lymphoma, and 7% had non-Hodgkin lymphoma.
Eighty-six percent of subjects had received chemotherapy, and 59% received radiation.
Results
Subjects were considered to have hypertension if their systolic blood pressure was 140 or greater, their diastolic blood pressure was 90 or greater, or if they had been previously diagnosed with hypertension and were taking antihypertensive medication.
The prevalence of hypertension was 2.6 times higher among CCSs than expected, based on age-, sex-, race- and body mass index-specific rates in the general population.
In addition, the incidence of hypertension increased for CCSs over time. Thirteen percent of CCSs had hypertension at age 30, 37% had it at age 40, and more than 70% had it at age 50.
Dr Gibson said rates of hypertension in CCSs matched rates in the general population of people about a decade older.
The researchers identified several factors that were significantly associated with hypertension among CCSs, including:
- Male sex (odd ratio [OR], 1.38; 95% CI, 1.14–1.67)
- Non-Hispanic black race (OR, 1.66; 95% CI, 1.28–2.16)
- Older age at assessment (OR per 1 year of age, 1.10; 95% CI, 1.08–1.11)
- Being overweight (OR, 1.58; 95% CI, 1.21–2.07)
- Obesity (OR, 3.02; 95% CI, 2.34–3.88).
Exposure to any type of radiation or chemotherapy was not significantly associated with hypertension, but nephrectomy was (OR, 1.68; 95% CI, 1.11–2.53).
Dr Gibson said the lack of an association between hypertension and radiation/chemotherapy was surprising. It suggests the connection between childhood cancer survival and adult hypertension is multifactorial and worthy of future research.
In the meantime, he said, clinicians should be mindful that CCSs are more likely than the general public to develop hypertension.
“The good news is that, unlike prior cancer therapy, high blood pressure is a modifiable risk factor,” Dr Gibson noted. “Research is needed to identify effective interventions to prevent hypertension in survivors, but our results emphasize the importance of blood pressure surveillance and management.”
Dr Gibson said a limitation of this study is that it was based on blood pressure measurements taken at a single study visit. A clinical diagnosis of hypertension typically requires measurements taken at multiple intervals.
In addition, the St. Jude Lifetime Cohort is a group of CCSs who undergo frequent clinical follow-up, so its participants may have benefited from being monitored and may therefore be in better health than CCSs who have less comprehensive follow-up.